Blood Transfusion and Organ Transplantation
W. B. Ross, P. L. Yap SUMMA R Y. During the last two decades it has been shown that blood transfusion enhances renal allograft survival. Recently, the introduction of cyclosporin A as the leading immunosuppressive agent has generally improved results and the relevance of blood transfusion to organ transplantation is now questioned. This review summa&es the vast amount of knowledge on the ‘blood transfusion effect in renal transplantation’, and we cite important clinical studies of this topic to illustrate the various theories regarding the immune mechanisms responsible for these effects. We draw attention to the other immunomodulatory properties of blood transfusion which may be related to those associated with transplantation. In particular, we examine the possibility that perioperative blood transfusion may have a detrimental effect on the survival of cancer patients.
Patients with chronic renal failure often develop anaemia and this topic has been reviewed recently in this journal.’ This type of anaemia is particularly marked when the patients are treated with haemodialysis rather than peritoneal dialysis. Patients with renal failure can be maintained on haemodialysis for many years. Many of these patients will require blood transfusion for symptomatic relief of anaemia and in the early days of dialysis, transfusions were given liberally. However, in 1966 Kissemeyer-Nielsen and colleagues reported two cases of hyperacute rejection of renal transplants. ’ They found lymphocytotoxic antibodies in the preoperative serum of the recipients. It was said that these patients had been ‘heavily isoimmunised by blood transfusions’ and they suggested that the pretransplant transfusions were responsible for the production of the lymphocytotoxic antibodies which were directed against the donor cells. This finding resulted in highly restrictive trans-
W. B. Ross, University Department of Surgery, P. L. Yap, Edinburgh and South East Scotland Regional Blood Transfusion Centre, Royal Infinnary, Edinburgh EH3 9HB. UK. Correspondence to: Dr P. L. Yap. Blood Reviews (1990) 4.252-258 0 1990 Longman GroupUK Ltd
fusion policies for potential renal transplant recipients. It also led to a greater use of lymphocyte crossmatches which are so important in renal transplantation today. It was subsequently confirmed that patients waiting for a renal transplant who have preformed lymphocytotoxic antibodies in their serum have a smaller chance of receiving a successful graft.3 Opelz also studied cytotoxic antibodies in patients who were while on haemodialysis.4 regularly transfused Patients with no demonstrable cytotoxic antibodies for more than 1 year before transplantation had a significantly better graft survival than patients who had no cytotoxic antibodies for less than a year prior to transplantation. Cytotoxic antibodies only developed in half of the patients who received regular blood transfusions. They suggested that those patients who did not develop antibodies represented a group of ‘non-responders’ who were more likely to accept a renal graft. In 1973, Gerhard Opelz and his co-workers reported retrospective studies on a group of 148 renal transplant recipients.5 They were surprised to find that patients with a total of more than 10 pretrans0268-960X/90/ONI.G0252
$10.00
BLOOD REVIEWS
plant transfusions had the highest survival compared to patients not transfused and transfused patients who received less than 10 transfusions of blood. The 1 year graft survival rate for the heavily transfused group was 66% compared with 43% for the patients receiving l-10 transfusions and 29% for non-transfused patients. Several retrospective studies followed and these confirmed the beneficial effect of blood transfusion. There has only been one attempt to compare pretransplant transfusion with no transfusion using a prospective randomised trial protocol.6 This confirmed a beneficial effect associated with transfusion.
253
blood cells. It is not known with certainty which population of leucocytes are responsible: monocytes and lymphocytes are candidates. Platelets only have MHC class I antigens and are therefore less likely to be involved. The benefit on graft survival increases with the number of transfusions given.r4 This has been confirmed by several studies. Opelz reviewed data from 200 transplant centres and was able to study nearly 7000 transplant recipients.r5 Patients who had received 6-10 transfusions had the highest 1 year survival rates. However, patients who had received more than 10 transfusions had a lower graft survival rate.
Amount, Type, and Timing of the Transfusion Various factors influence renal graft survival (Table 1). However, does the amount, type and timing of blood transfusion influence the observed beneficial effect? Stiller et al reported that transfusion given on the day of transplantion improved graft survival in patients who had not been transfused previously and also in patients who had received pretransplant transfusions.7 This retrospective study also confirmed the beneficial effect of pretransplant transfusion on graft survival at 1 year (7 1% for transfused and 40% for non-transfused). Corry et al found that transfusions given at the time of surgery had a beneficial effect, but other studies have failed to confirm thisa*’ Hourmant et al demonstrated a small benefit in patients transfused within 3 months prior to transplantation compared with patients transfused at an earlier stage.” Pretranspiant transfusion usually consists of whole blood or packed red cells. Both types of blood improve graft survival. Packed cells possibly exert a greater effect than whole blood and frozen blood preparations do not influence graft outcome.” Leucocyte-poor blood can be produced by filtering with cotton wool and it does not have an effect on graft survival, possibly because not all leucocytes are removed by this process. ‘* The same report showed that leucocyte-poor blood (washed red cells) did exert a beneficial effect compared with blood that was completely leucocyte-free. Rapaport and Dausset have demonstrated that blood leucocyte extracts enhance skin allograft survival in humans.13 The leucocytes express class I and class II MHC i.e. HLA A,B and DR antigens whereas red blood cells do not, a situation that differs from that in rats and mice where histocompatibility antigens are also present on red
Live Donor Renal Transplantation
Salvatierra first reported the beneficial effects of donor specific transfusion in live-related donor renal transplants.16 This study demonstrated a highly significant survival advantage for transfused recipients of a 1 HLA-haplotype matched live related donor kidney. Similar effects have been demonstrated by others.17 A hazard of donor specific transfusion is sensitisation with the appearance of anti-donor Tlymphocyte antibodies which will prohibit transplantation to proceed. This may occur in up to 30% of cases, but anti-donor sensitisation can be abolished by concomitant administration of azathioprine and more recently cyclosporin with donor specific transfusion prior to transplantation; however, donor specific transfusion may be associated with earlier severe rejection episodes. l* The situation is confused by the recent finding that when compared with random donor transfusions, donor specific transfusion may not have a superior beneficial effect.lg This study also indicated that the transfusion effect present at 1 year after transplant was not seen at 3 years i.e. transfused and non-transfused patients had similar long-term graft survival rates. Role of HLA Typing
Iwaki et al have shown that if there was no HLA-DR mismatch there was no beneficial effect of transfusion.*’ However, transfusions improved 1 year graft survival rates by 8% for transplant recipients with 1 DR-mismatched grafts, and by 10% for recipients with 2 DR-mismatched grafts. It would seem that although the blood transfusion effect is becoming less apparent, it should still be considered for patients without complete DR matching.
Table 1 Some factors that influence renal graft survival Immunosuppressive therapy (azathioprine, cyclosporin, steroids etc) Degree of HLA matching Previous transplants and pregnancies Presence of lymphocytotoxic antibodies ABO blood group Organ preservation prior to transplantation Blood transfusion
Transfusion, Transplantation and Cyclosporin
The latest update on the Collaborative Transplant Study published in 1989 indicates that the influence of pretransplant transfusion on graft survival has been diminishing since 1984. lg This study includes 17 000 patients (90% were transfused) and still demonstrates
254
BLOOD TRANSFUSION
AND ORGAN TRANSPLANTATION
60
111 . . , . , , . . , *. ,: 0
6
3 Time
3
12
0
3 Time
(Months1
........
>o
n-1621
. .........
>O
n-15228
____
0
n=
____
0
n=
138
6 tMonths1
9
12
1731
Fig. 1 Effect of pretransplant blood transfusions on outcome of first cadaver kidney transplants. Transplants performed 1982-l 983 (left) are compared with transplants performed 1984-l 987 (right). All patients were immunosuppressed Reproduced with permission from Transplantation Proceedings.
a small significant beneficial effect associated with transfusion, but it would seem that the risks of sesitisation and disease transmission may now outweigh this small advantage (Fig. l).‘l
with cyclosporin.
accepted. 22 This means that only non-responders would be selected because of their inability to produce lymphocytotoxic antibodies. Specific Humoral Factors: Anti-idiotypic Antibodies
Mechanisms
This represents the simplest explanation. Some patients respond to blood transfusion, and also respond to pregnancy, by forming lymphocytotoxic antibodies that may eliminate them as potential graft recipients as described above or only allows the patient to receive a kidney which is more likely to be
Anti-idiotypic antibodies are antibodies directed against an idiotype, a unique antigenic determinant present in the variable region of an antibody molecule. These can be induced by blood transfusion and have been shown to induce immunological unresponsiveness.23 This can be measured in several ways, including inhibition of T-lymphocyte responses in graft versus host reactions; mixed lymphocyte culture and cell-mediated lympholysis reactions.24 Singal and Joseph were the first to report this potential mechanism in transplant recipients. The anti-idiotypic antibodies were not present in patients who had rejected the transplant. It has been shown that the inhibitory antibody is specific for responder cell from the recipient of the blood and transplant. Inhibition in mixed lymphocyte culture is not mediated by antibodies against common surface antigens on either the responder or stimulator lymphocyte-the antibodies are directed against specific recognition sites on T-lymphocytes, hence the term-anti-idiotypic antibodies. It is also known that these antibodies are present for considerable lengths of time and their development is related to the histocompatibility between recipient and donor.
Table 2 Potential mechanisms for the immunosuppressive effect of blood transfusions in renal transplantation
Non-spec$c
Selection of non-responders Anti-idiotypic antibodies Non-specific immunosuppression -macrophage PGE2 -altered lymphocyte responses -plasma factors Suppressor cell induction Clonal deletion
Non-specific immunosuppression by macrophages has been suggested. 25 In this context, the term nonspecific relates to antigenic specificity e.g. HLA antigens. They suggested that endocytosis of damaged red cells from the transfused blood impaired normal mononuclear phagocytic function. They postulated that endocytosis might generate prostaglandin which
Much research has been directed towards identifying the mechanisms involved in mediating the beneficial effects of blood transfusion on renal graft survival. Two decades have passed and the problem has not been solved. Multiple mechanisms may be involved because no one theory adequately explains all the known effects of blood transfused (Table 2). In addition, blood is a mixture of different cellular elements and plasma constituents that is transfused from one immunologically distinct individual to another and one effect may be more important in one patient than another. Some of this work will be reviewed to illustrate the theories which have been put forward. Selection of Non-responders
Immunosuppression
BLOOD REVIEWS
could induce suppressor cells. Watson et al measured cell-mediated immunity by skin testing with dinitrochlorobenzene.26 The degree of skin reaction to this chemical is a measure of cell-mediated immune function. They found that patients with weak reactions had a higher graft survival after transplantation and that the weak responders had had more pretransplant transfusions. In fact the patients who were weak responders were more anaemic than strong responders so these findings could not support a theory which suggested that blood transfusion caused a general suppression of cell-mediated immunity. However, this is a difficult area to study without some attempt to purify the potential non-specific factors. Altered Lymphocyte Responses
Another group assessed cell-mediated immunity by measuring the lymphocyte responses to mitogenic and antigenic stimulation. *’ Non-transfused prospective kidney transplant recipients were transfused with washed red cells. They found a reduced lymphocyte response after transfusion. A second transfusion led to a more pronounced and prolonged suppression of this. response. Normal volunteers were given transfusions of autologous blood, but no suppression of cell mediated immunity was found. Kerman et al assessed cellular immunity by testing spontaneous lymphocyte blastogenesis, skin test antigen responses, lymphocyte response to alloantigen and mononuclear suppressor cell activity.*’ Patients who received more than 5 pretransplant transfusions were found to be weak immune responders and have a strong in vitro suppressor cell function. They suggested that these ‘traits’ may explain the beneficial effect of transfusion on graft survival.
255
patients on chronic haemodialysis who receive multiple transfusion have comparatively high levels of prostaglandin E in their blood.31-33 Administration of prostaglandin has been shown to prolong the survival of murine skin allografts while prostaglandin synthetase inhibitors decrease graft survival.34 It has been shown that indomethacin blocks the blood transfusion induced immunosuppression associated with a prolonged graft survival in a rat heart transplant model. 35 They also demonstrated that antiPGE antibody blocked allogeneic blood induced suppression by neutralising endogenous PGE in the experimental animals. Waymack investigated the effect of transfusions on the production of arachidonic acid metabolites by cultured macrophages. 36 Using a rat model they demonstrated that allogeneic blood transfusions were associated with increased macrophage production of prostaglandin E2. Two Stage Theory
Another theory suggests a two stage process.37 Firstly there is a non-specific suppression of cytotoxic lymphocyte reactivity and induction of antiHLA class I (A,B,C) antibodies. Then specific anti-HLA antibodies are produced which prevent activation of T-lymphocytes by class I and class II (D,DR) in the donor blood. These antibodies may subsequently block host T-lymphocyte activation in response to class I antigens on the graft. This theory explains why transfusion with HLA-matched blood exerts no beneficial effect on graft survival.38 It must be noted that HLA typing at that time only allowed classification of class I antigens and HLA-D,DR typing could not be performed on the patients involved.
Suppressor Cell Induction
A group in Cardiff showed that blood transfusion was associated with increased suppressor cell function in patients undergoing haemodialysis.29 This method involved con-A lymphocyte stimulation before and after cell culture. Suppressive activity is lost during culture, but is retained if suppressor activity is high. Lenhard et al showed that blood transfusion suppressed the mixed lymphocytic reaction and increased the number of monocytes. 3o The mixed lymphocytic reaction returned to normal after removal of the monocytes. They suggested that monocytes act as suppressor cells. They also found that T-cell suppressor activity increased later on in the post-transfusion period suggesting that at least two immunoregulatory mechanisms may be induced by blood transfusion. Macrophages and Prostaglandins
Further interest has developed, centred on the role of the macrophage as a suppressor cell. It is known that
Clonal Deletion Theory
Terasaki proposed the clonal deletion theory.39 This suggests that blood transfusion can exert a beneficial effect only in the presence of immunosuppressive therapy. Multiple blood transfusion will sensitise recipients to a wide range of antigens. After transplantation, a rapid immune response is directed against previously encountered antigens present on the graft. However, the presence of immunosuppressive therapy at the time of grafting deletes the clones of reactive lymphocytes. Of these proposed mechanisms we conclude that the clonal deletion theory is attractive but difficult to test for since there is a need for some way of identifying clones. Similarly, study of the antiidiotypic mechanism needs special techniques. In any case, with good (> 80%) 1 year graft survival being achieved, it is now very difficult to further investigate these mechanisms clinically.
256
BLOOD TRANSFUSION AND ORGAN TRANSPLANTATION
Other Possible Immunosuppressive Effects of Blood Transfusion If blood transfusion causes a non-specific immunosuppressive effect in renal transplant recipients, then can this effect occur in other situations? Much attention has been focused recently on the possible detrimental effects on survival of perioperative blood transfusion in patients undergoing cancer surgery. Malignancy
Burrows and Tartter were the first to present clinical data which suggested a detrimental effect of blood transfusion in colorectal cancer patients.40 Since then, over 30 retrospective studies of this type have been reported: a third of these show a statistically significant survival disadvantage associated with transfusion; a third show a similar trend which is not significant and the remainder show no difference.41,42 Findings are less clear when other cancers are studied, but again several studies suggest a detrimental effect of blood transfusion in breast, kidney, prostate, gastric, uterine cervical, head and neck, and soft tissue sarcoma. 41 It would appear that blood transfusion may be associated with a poorer prognosis. This may be due to immunosuppressive mechanisms similar to those which may affect renal transplantation, or it may be related to the possibility that transfused patients have more advanced malignancy.43 Prospec-
tive, randomised trials are required to produce conclusive data; such, multicentre trials are now underway, and their results are awaited. Postoperative Infective Complications
One prospective study has shown that perioperative blood transfusion is associated with increased morbidity due to postoperative infective complications.44 Inflammatory Bowel Disease
There is also evidence that perioperative blood transfusion may decrease recurrence rates after bowel resection for Crohn’s disease (a beneficial effect).4s However, as with the retrospective studies concerning cancer, this report now ranks amongst several other which give conflicting conclusions about the role of blood transfusion in the management of Crohn’s disease. Recurrent Spontaneous Abortions
Recurrent abortion may result from deranged immune function which prevents rejection of the fetus during normal pregnancy. It has been established, for example, that sharing of HLA antigens is more frequent than normal amongst couples who suffer abortions. Recurrent abortions have now been suc-
YEARSSINCE TRANSPLANTATION Fig. 2 Continued year on year improvement in renal graft survival. Source: United Kingdom Transplant Service, Bristol.
BLOOD REVIEWS
cessfully treated by immunisation with paternal cells, and with leukocytes from third-party donors in some women in studies with relatively small groups of patients. 46,47 The results, although promising are complicated by the need for control groups of adequate size and the exact role of such immunotherapy in recurrent spontaneous abortions remains unclear. Conclusions Blood transfusion may still exert a beneficial effect on renal graft survival. In general, this is now only a small advantage because of cyclosporin and other advances which have enhanced graft survival. Blood transfusion may have a role in specific subsets of recipients, such as those with HLA-DR mismatches or in those patients receiving a second or third graft. The seemingly endless improvements which have led to very good renal graft survival now give rise to difficulties in the dissection of contributions by each of the postulated mechanisms of transfusion-mediated immunosuppression (Fig. 2). There remains the risks of sensitisation and infection and these risks are presently considered by some to outweigh the potential benefits of pretransplant transfusion. However, at present, on the basis of available evidence, we recommend an elective pretransplant transfusion of three units of red cell concentrate. Should anaemia continue to be a problem, then we suggest the use of erythropoietin or if necessary the use of leucocytedepleted blood, although evidence to support the latter course is not yet obtainable. In conclusion, pretransplant transfusion remains a cheap and effective immunosuppressive agent which should remain part of the management of patients for renal transplantation. References 1. Schiller G J, Berkman S A 1989 Haematologic aspects of
renal insufficiency. Blood Reviews 3: 141-146 2. Kissmeyer-Nielsen F, Olsen S, Petersen V P, Fjeldborg 0 1966 Hyperacute rejection of kidney allografts associated with pre-existing humoral antibodies against donor cells. Lancet i: 662-665 3. Opelz G, Terasaki P I 1972 Histocompatibility matching utilizing responsiveness as a new dimension. Transplantation Proceedings 4: 433-437 4. Opelz G, Mickey M R, Terasaki P I 1972 Identification of unresponsive kidney transplant recipients. Lancet i: 868-871 5. Opelz G, Sengar D P S, Mickey M R, Terasaki P I 1973 Effect of blood transfusions on subsequent kidney transplants. Transplantation Proceedings 4 433-437 6. Bucin D, Lindholm T, Low B, Husberg B 1981 Blood transfusion and kidney transplantation. Scandinavian Journal of Urology and Nephrology 64-89 I. Stiller C R, Lockwood B L, Sinclair N R, Ulan R A, Sheppard R R, Sharpe J A, Hayman P 1978 Beneficial effect of operation-day blood transfusions on human renal allograft survival. Lancet i: 169-170 8. Corry R J, West J C, Hunsicker L G, Schabacher B A, Lachenbruch P A 1980 Effect of timing of administration and quantity of blood transfusion on cadaver& renal transplant survival. Transplantation 1980 30: 425-428 9. Qpelz G, Terasaki P I 1981 Importance of preoperative (not peroperative) transfusions for cadaver kidney transplants. Transplantation 31: 106108
257
10. Hourmant M, Soulillou J P, Bui-Quang D 1979 Beneficial effect of blood transfusion. Transplantation 28: 40-43 11. Qpelz G, Terasaki P I 1980 Dominant effect of transfusions on kidney graft survival. Transplantation 29: 153-158 12. Persijn G G, Cohen B, Lansbergen Q, van Rood J J 1979 Retrospective and prospective studies on the effect of blood transfusions in renal transplantation in the Netherlands. Transplantation 2% 396-408 13. Rapaport F T, Dausset J 1984 Facilitation of skin allograft survival by blood leucoyte extracts. Annals of Surgery 199: 79-86 14. Opelz G, Terasaki P I 1978 Improvement of kidney graft survival with increased numbers of blood transfusions. New England Journal of Medicine 299: 799-803 15. Opelz G 1985 Current relevance of the transfusion effect in renal transplantation. Transplantation Proceedings 17: 1015-1022 16. Salvatierra 0 Jr, Vincenti F, Amend W et al 1980 Deliberate donor-specific blood transfusions prior to living related donor transplantation. A new approach. Annals of Surgery 192: 543-552 17. Glass N R, Miller D T, Sollinger H W, Belzer F 0 1985 A four-year experience with donor blood transfusion protocols for living-donor renal transplantation. Transplantation 39: 615-619 18. Sells R A, Scott M H, Prieto M, Bone J M, Evans G M, Millar R, Hillis A N 1989 Early rejection following donorspecific transfusion prior to HLA-mismatched living related renal transplantation. Transplantation Proceedings 21: 1173-1174 19. Opelz G 1989 The role of HLA matching and blood transfusions in the cyclosporine era. Transplantation Proceedings 21: 609-612 20. Iwaki Y, Cecka J M, Terasaki P I 1990 The transfusion effect in cadaver kidney transplants-yes or no. Transplantation 49: 56-59 21. Anonymous 1988 Time to abandon pre-transplant blood transfusion. Lancet i: 567-568 22. D’Apice A J F. Tait B D 1982 An elective transfusion policy: sensitization rates, patient transplantability, and transplant outcome. Transplantation 33: 191-195 23. Singal D P. Joseoh S 1982 Role of blood transfusions on the indiction of ant;bodies against recognition sites on T lymphocytes in renal transplant patients. Human Immunology 4: 93-108 24. Binz H, Wigzell H 1976 Specific transplantation tolerance induced by autoimmunization against the individual’s own, naturally occurring idiotypic, antigen-binding receptors. Journal of Experimental Medicine 144: 1438-1457 25. Keown P A. Descamps B 1979 Improved renal allograft survival after blood transfusion: a non-specific, erythrocytemediated immunoregulatory process? Lancet i: 20-22 26. Watson M A, Briggs J D, Diamandopoulos A A, Hamilton D N H, Dick H M 1979 Endogenous cell-mediated immunity, blood transfusion, and outcome of renal transplantation. Lancet ii: 1323-1326 27. Fischer E, Lenhard V, Seifert P, Kluge A, Johannsen R 1980 Blood transfusion-induced suppression of cellular immunity in man. Human Immunology 3: 187-194 28. Kerman R H, Van Buren C T, Payne W et al 1983 The influence of pretransplant blood transfusions from random donors on immune parameters affecting cadaveric allograft survival. Transplantation 36: 50-54 29. Smith M D, Williams J D, Coles G A, Salaman J R 1983 Blood transfusion, suppressor T cells, and renal transplant survival. Transplantation 36: 647-650 30. Lenhard V, Massen G, Seifert P, Johannsen R, GrosseWilde H 1982 Characterization of transfusion-induced suppressor cells in prospective kidney allograft recipients. Transplantation Proceedings 14: 329-332 31. Lenhard V, Gesma D, Opelz G 1985 Transfusion induced release of prostaglandin E2 and its role in the activation of T suppressor cells. Transplantation Proceedings 17: 2380-2382 32. Jackson V, Tsakus D, Tonner E, Briggs J D, Junor B J R 1985 In vitro prostaglandin E production following multiple blood transfusions in dialysis patients. Transplantation Proceedings 17: 2386-2389 _ 33. Roy R, Lachance J G, Beaudoin R, Grose J H, Noel R 1985 Prostaglandin-dependent suppressor factor induced following
258
34.
35.
36.
31. 38.
39.
40.
BLOOD TRANSFUSION
AND ORGAN TRANSPLANTATION
l-5 blood transfusions: role in kidney graft outcome. Transplantation Proceedings 17: 2382-2385 Anderson C B, Jaffee B M, Gratf R J 1977 Prolongation of murine skin allografts by prostaglandin E 1. Transplantation 23: 444-441 Shelby J, Marushack M M, Nelson E W 1987 Prostaglandin production and suppressor cell induction in transfusioninduced immune suppression. Transplantation 43: 113-l 16 Waymack J P, Gallon L, Barcelli U, Trocki 0, Alexander J W 1987 Effects of blood transfusion on immune function. III. Alterations in macrophage arachidonic acid metabolism. Archives of Surgery 122: 56-60 Van Rood J J 1983 Pretransplant blood transfusion: sure! But how and why? Transplantation Proceedings 15: 915-916 Albert E D, Scholz S, Meixner U, Land W 1981 HLA-A,B matching of pretransplant blood transfusion is associated with poor graft survival. Transplantation Proceedings 13: 175-177 Terasaki P I 1984 The beneficial transfusion effect on kidney graft survival attributed to clonal deletion. Transplantation 37: 119-125 Burrows L, Tartter P 1982 Effect of blood transfusions on colonic malignancy recurrence rate. Lancet ii: 662
41. Salo M 1988 Immunosuppressive effects of blood transfusion in anaesthesia and surgery. Acta Anaethesiologica Scandinavica 39: Supplement 89: 26-34 42. Blumberg N, Heal J M 1989 Transfusion and host defenses against cancer recurrence and infection. Transfusion 29: 236-245 43. Ross W B 1987 Blood transfusion and colorectal cancer. Journal of the Royal College of Surgeons of Edinburgh 32: 197-201 44. Tartter P I 1989 Blood transfusion and postoperative infections. Transfusion 29: 456-459 45. Williams J G, Hughes L E 1989 Effect of perioperative blood transfusion on recurrence of Crohn’s disease. Lancet ii: 131-133 46. Mowbray J F, Gibbings C, Liddell H, Reginald P W, Underwood J L, Beard R W 1985 Controlled trial of treatment of recurrent spontaneous abortion by immunisation with paternal cells. Lancet i: 941-943 41. Unander A M, Lindholm A 1986 Transfusions of leukocyterich erythrocyte concentrates; a successful treatment in selected cases of habitual abortion. American Journal of Obstetrics and Gynecology 154: 516-520
W. B. Ross, P. L. Yap SUMMA R Y. During the last two decades it has been shown that blood transfusion enhances renal allograft survival. Recently, the introduction of cyclosporin A as the leading immunosuppressive agent has generally improved results and the relevance of blood transfusion to organ transplantation is now questioned. This review summa&es the vast amount of knowledge on the ‘blood transfusion effect in renal transplantation’, and we cite important clinical studies of this topic to illustrate the various theories regarding the immune mechanisms responsible for these effects. We draw attention to the other immunomodulatory properties of blood transfusion which may be related to those associated with transplantation. In particular, we examine the possibility that perioperative blood transfusion may have a detrimental effect on the survival of cancer patients.
Patients with chronic renal failure often develop anaemia and this topic has been reviewed recently in this journal.’ This type of anaemia is particularly marked when the patients are treated with haemodialysis rather than peritoneal dialysis. Patients with renal failure can be maintained on haemodialysis for many years. Many of these patients will require blood transfusion for symptomatic relief of anaemia and in the early days of dialysis, transfusions were given liberally. However, in 1966 Kissemeyer-Nielsen and colleagues reported two cases of hyperacute rejection of renal transplants. ’ They found lymphocytotoxic antibodies in the preoperative serum of the recipients. It was said that these patients had been ‘heavily isoimmunised by blood transfusions’ and they suggested that the pretransplant transfusions were responsible for the production of the lymphocytotoxic antibodies which were directed against the donor cells. This finding resulted in highly restrictive trans-
W. B. Ross, University Department of Surgery, P. L. Yap, Edinburgh and South East Scotland Regional Blood Transfusion Centre, Royal Infinnary, Edinburgh EH3 9HB. UK. Correspondence to: Dr P. L. Yap. Blood Reviews (1990) 4.252-258 0 1990 Longman GroupUK Ltd
fusion policies for potential renal transplant recipients. It also led to a greater use of lymphocyte crossmatches which are so important in renal transplantation today. It was subsequently confirmed that patients waiting for a renal transplant who have preformed lymphocytotoxic antibodies in their serum have a smaller chance of receiving a successful graft.3 Opelz also studied cytotoxic antibodies in patients who were while on haemodialysis.4 regularly transfused Patients with no demonstrable cytotoxic antibodies for more than 1 year before transplantation had a significantly better graft survival than patients who had no cytotoxic antibodies for less than a year prior to transplantation. Cytotoxic antibodies only developed in half of the patients who received regular blood transfusions. They suggested that those patients who did not develop antibodies represented a group of ‘non-responders’ who were more likely to accept a renal graft. In 1973, Gerhard Opelz and his co-workers reported retrospective studies on a group of 148 renal transplant recipients.5 They were surprised to find that patients with a total of more than 10 pretrans0268-960X/90/ONI.G0252
$10.00
BLOOD REVIEWS
plant transfusions had the highest survival compared to patients not transfused and transfused patients who received less than 10 transfusions of blood. The 1 year graft survival rate for the heavily transfused group was 66% compared with 43% for the patients receiving l-10 transfusions and 29% for non-transfused patients. Several retrospective studies followed and these confirmed the beneficial effect of blood transfusion. There has only been one attempt to compare pretransplant transfusion with no transfusion using a prospective randomised trial protocol.6 This confirmed a beneficial effect associated with transfusion.
253
blood cells. It is not known with certainty which population of leucocytes are responsible: monocytes and lymphocytes are candidates. Platelets only have MHC class I antigens and are therefore less likely to be involved. The benefit on graft survival increases with the number of transfusions given.r4 This has been confirmed by several studies. Opelz reviewed data from 200 transplant centres and was able to study nearly 7000 transplant recipients.r5 Patients who had received 6-10 transfusions had the highest 1 year survival rates. However, patients who had received more than 10 transfusions had a lower graft survival rate.
Amount, Type, and Timing of the Transfusion Various factors influence renal graft survival (Table 1). However, does the amount, type and timing of blood transfusion influence the observed beneficial effect? Stiller et al reported that transfusion given on the day of transplantion improved graft survival in patients who had not been transfused previously and also in patients who had received pretransplant transfusions.7 This retrospective study also confirmed the beneficial effect of pretransplant transfusion on graft survival at 1 year (7 1% for transfused and 40% for non-transfused). Corry et al found that transfusions given at the time of surgery had a beneficial effect, but other studies have failed to confirm thisa*’ Hourmant et al demonstrated a small benefit in patients transfused within 3 months prior to transplantation compared with patients transfused at an earlier stage.” Pretranspiant transfusion usually consists of whole blood or packed red cells. Both types of blood improve graft survival. Packed cells possibly exert a greater effect than whole blood and frozen blood preparations do not influence graft outcome.” Leucocyte-poor blood can be produced by filtering with cotton wool and it does not have an effect on graft survival, possibly because not all leucocytes are removed by this process. ‘* The same report showed that leucocyte-poor blood (washed red cells) did exert a beneficial effect compared with blood that was completely leucocyte-free. Rapaport and Dausset have demonstrated that blood leucocyte extracts enhance skin allograft survival in humans.13 The leucocytes express class I and class II MHC i.e. HLA A,B and DR antigens whereas red blood cells do not, a situation that differs from that in rats and mice where histocompatibility antigens are also present on red
Live Donor Renal Transplantation
Salvatierra first reported the beneficial effects of donor specific transfusion in live-related donor renal transplants.16 This study demonstrated a highly significant survival advantage for transfused recipients of a 1 HLA-haplotype matched live related donor kidney. Similar effects have been demonstrated by others.17 A hazard of donor specific transfusion is sensitisation with the appearance of anti-donor Tlymphocyte antibodies which will prohibit transplantation to proceed. This may occur in up to 30% of cases, but anti-donor sensitisation can be abolished by concomitant administration of azathioprine and more recently cyclosporin with donor specific transfusion prior to transplantation; however, donor specific transfusion may be associated with earlier severe rejection episodes. l* The situation is confused by the recent finding that when compared with random donor transfusions, donor specific transfusion may not have a superior beneficial effect.lg This study also indicated that the transfusion effect present at 1 year after transplant was not seen at 3 years i.e. transfused and non-transfused patients had similar long-term graft survival rates. Role of HLA Typing
Iwaki et al have shown that if there was no HLA-DR mismatch there was no beneficial effect of transfusion.*’ However, transfusions improved 1 year graft survival rates by 8% for transplant recipients with 1 DR-mismatched grafts, and by 10% for recipients with 2 DR-mismatched grafts. It would seem that although the blood transfusion effect is becoming less apparent, it should still be considered for patients without complete DR matching.
Table 1 Some factors that influence renal graft survival Immunosuppressive therapy (azathioprine, cyclosporin, steroids etc) Degree of HLA matching Previous transplants and pregnancies Presence of lymphocytotoxic antibodies ABO blood group Organ preservation prior to transplantation Blood transfusion
Transfusion, Transplantation and Cyclosporin
The latest update on the Collaborative Transplant Study published in 1989 indicates that the influence of pretransplant transfusion on graft survival has been diminishing since 1984. lg This study includes 17 000 patients (90% were transfused) and still demonstrates
254
BLOOD TRANSFUSION
AND ORGAN TRANSPLANTATION
60
111 . . , . , , . . , *. ,: 0
6
3 Time
3
12
0
3 Time
(Months1
........
>o
n-1621
. .........
>O
n-15228
____
0
n=
____
0
n=
138
6 tMonths1
9
12
1731
Fig. 1 Effect of pretransplant blood transfusions on outcome of first cadaver kidney transplants. Transplants performed 1982-l 983 (left) are compared with transplants performed 1984-l 987 (right). All patients were immunosuppressed Reproduced with permission from Transplantation Proceedings.
a small significant beneficial effect associated with transfusion, but it would seem that the risks of sesitisation and disease transmission may now outweigh this small advantage (Fig. l).‘l
with cyclosporin.
accepted. 22 This means that only non-responders would be selected because of their inability to produce lymphocytotoxic antibodies. Specific Humoral Factors: Anti-idiotypic Antibodies
Mechanisms
This represents the simplest explanation. Some patients respond to blood transfusion, and also respond to pregnancy, by forming lymphocytotoxic antibodies that may eliminate them as potential graft recipients as described above or only allows the patient to receive a kidney which is more likely to be
Anti-idiotypic antibodies are antibodies directed against an idiotype, a unique antigenic determinant present in the variable region of an antibody molecule. These can be induced by blood transfusion and have been shown to induce immunological unresponsiveness.23 This can be measured in several ways, including inhibition of T-lymphocyte responses in graft versus host reactions; mixed lymphocyte culture and cell-mediated lympholysis reactions.24 Singal and Joseph were the first to report this potential mechanism in transplant recipients. The anti-idiotypic antibodies were not present in patients who had rejected the transplant. It has been shown that the inhibitory antibody is specific for responder cell from the recipient of the blood and transplant. Inhibition in mixed lymphocyte culture is not mediated by antibodies against common surface antigens on either the responder or stimulator lymphocyte-the antibodies are directed against specific recognition sites on T-lymphocytes, hence the term-anti-idiotypic antibodies. It is also known that these antibodies are present for considerable lengths of time and their development is related to the histocompatibility between recipient and donor.
Table 2 Potential mechanisms for the immunosuppressive effect of blood transfusions in renal transplantation
Non-spec$c
Selection of non-responders Anti-idiotypic antibodies Non-specific immunosuppression -macrophage PGE2 -altered lymphocyte responses -plasma factors Suppressor cell induction Clonal deletion
Non-specific immunosuppression by macrophages has been suggested. 25 In this context, the term nonspecific relates to antigenic specificity e.g. HLA antigens. They suggested that endocytosis of damaged red cells from the transfused blood impaired normal mononuclear phagocytic function. They postulated that endocytosis might generate prostaglandin which
Much research has been directed towards identifying the mechanisms involved in mediating the beneficial effects of blood transfusion on renal graft survival. Two decades have passed and the problem has not been solved. Multiple mechanisms may be involved because no one theory adequately explains all the known effects of blood transfused (Table 2). In addition, blood is a mixture of different cellular elements and plasma constituents that is transfused from one immunologically distinct individual to another and one effect may be more important in one patient than another. Some of this work will be reviewed to illustrate the theories which have been put forward. Selection of Non-responders
Immunosuppression
BLOOD REVIEWS
could induce suppressor cells. Watson et al measured cell-mediated immunity by skin testing with dinitrochlorobenzene.26 The degree of skin reaction to this chemical is a measure of cell-mediated immune function. They found that patients with weak reactions had a higher graft survival after transplantation and that the weak responders had had more pretransplant transfusions. In fact the patients who were weak responders were more anaemic than strong responders so these findings could not support a theory which suggested that blood transfusion caused a general suppression of cell-mediated immunity. However, this is a difficult area to study without some attempt to purify the potential non-specific factors. Altered Lymphocyte Responses
Another group assessed cell-mediated immunity by measuring the lymphocyte responses to mitogenic and antigenic stimulation. *’ Non-transfused prospective kidney transplant recipients were transfused with washed red cells. They found a reduced lymphocyte response after transfusion. A second transfusion led to a more pronounced and prolonged suppression of this. response. Normal volunteers were given transfusions of autologous blood, but no suppression of cell mediated immunity was found. Kerman et al assessed cellular immunity by testing spontaneous lymphocyte blastogenesis, skin test antigen responses, lymphocyte response to alloantigen and mononuclear suppressor cell activity.*’ Patients who received more than 5 pretransplant transfusions were found to be weak immune responders and have a strong in vitro suppressor cell function. They suggested that these ‘traits’ may explain the beneficial effect of transfusion on graft survival.
255
patients on chronic haemodialysis who receive multiple transfusion have comparatively high levels of prostaglandin E in their blood.31-33 Administration of prostaglandin has been shown to prolong the survival of murine skin allografts while prostaglandin synthetase inhibitors decrease graft survival.34 It has been shown that indomethacin blocks the blood transfusion induced immunosuppression associated with a prolonged graft survival in a rat heart transplant model. 35 They also demonstrated that antiPGE antibody blocked allogeneic blood induced suppression by neutralising endogenous PGE in the experimental animals. Waymack investigated the effect of transfusions on the production of arachidonic acid metabolites by cultured macrophages. 36 Using a rat model they demonstrated that allogeneic blood transfusions were associated with increased macrophage production of prostaglandin E2. Two Stage Theory
Another theory suggests a two stage process.37 Firstly there is a non-specific suppression of cytotoxic lymphocyte reactivity and induction of antiHLA class I (A,B,C) antibodies. Then specific anti-HLA antibodies are produced which prevent activation of T-lymphocytes by class I and class II (D,DR) in the donor blood. These antibodies may subsequently block host T-lymphocyte activation in response to class I antigens on the graft. This theory explains why transfusion with HLA-matched blood exerts no beneficial effect on graft survival.38 It must be noted that HLA typing at that time only allowed classification of class I antigens and HLA-D,DR typing could not be performed on the patients involved.
Suppressor Cell Induction
A group in Cardiff showed that blood transfusion was associated with increased suppressor cell function in patients undergoing haemodialysis.29 This method involved con-A lymphocyte stimulation before and after cell culture. Suppressive activity is lost during culture, but is retained if suppressor activity is high. Lenhard et al showed that blood transfusion suppressed the mixed lymphocytic reaction and increased the number of monocytes. 3o The mixed lymphocytic reaction returned to normal after removal of the monocytes. They suggested that monocytes act as suppressor cells. They also found that T-cell suppressor activity increased later on in the post-transfusion period suggesting that at least two immunoregulatory mechanisms may be induced by blood transfusion. Macrophages and Prostaglandins
Further interest has developed, centred on the role of the macrophage as a suppressor cell. It is known that
Clonal Deletion Theory
Terasaki proposed the clonal deletion theory.39 This suggests that blood transfusion can exert a beneficial effect only in the presence of immunosuppressive therapy. Multiple blood transfusion will sensitise recipients to a wide range of antigens. After transplantation, a rapid immune response is directed against previously encountered antigens present on the graft. However, the presence of immunosuppressive therapy at the time of grafting deletes the clones of reactive lymphocytes. Of these proposed mechanisms we conclude that the clonal deletion theory is attractive but difficult to test for since there is a need for some way of identifying clones. Similarly, study of the antiidiotypic mechanism needs special techniques. In any case, with good (> 80%) 1 year graft survival being achieved, it is now very difficult to further investigate these mechanisms clinically.
256
BLOOD TRANSFUSION AND ORGAN TRANSPLANTATION
Other Possible Immunosuppressive Effects of Blood Transfusion If blood transfusion causes a non-specific immunosuppressive effect in renal transplant recipients, then can this effect occur in other situations? Much attention has been focused recently on the possible detrimental effects on survival of perioperative blood transfusion in patients undergoing cancer surgery. Malignancy
Burrows and Tartter were the first to present clinical data which suggested a detrimental effect of blood transfusion in colorectal cancer patients.40 Since then, over 30 retrospective studies of this type have been reported: a third of these show a statistically significant survival disadvantage associated with transfusion; a third show a similar trend which is not significant and the remainder show no difference.41,42 Findings are less clear when other cancers are studied, but again several studies suggest a detrimental effect of blood transfusion in breast, kidney, prostate, gastric, uterine cervical, head and neck, and soft tissue sarcoma. 41 It would appear that blood transfusion may be associated with a poorer prognosis. This may be due to immunosuppressive mechanisms similar to those which may affect renal transplantation, or it may be related to the possibility that transfused patients have more advanced malignancy.43 Prospec-
tive, randomised trials are required to produce conclusive data; such, multicentre trials are now underway, and their results are awaited. Postoperative Infective Complications
One prospective study has shown that perioperative blood transfusion is associated with increased morbidity due to postoperative infective complications.44 Inflammatory Bowel Disease
There is also evidence that perioperative blood transfusion may decrease recurrence rates after bowel resection for Crohn’s disease (a beneficial effect).4s However, as with the retrospective studies concerning cancer, this report now ranks amongst several other which give conflicting conclusions about the role of blood transfusion in the management of Crohn’s disease. Recurrent Spontaneous Abortions
Recurrent abortion may result from deranged immune function which prevents rejection of the fetus during normal pregnancy. It has been established, for example, that sharing of HLA antigens is more frequent than normal amongst couples who suffer abortions. Recurrent abortions have now been suc-
YEARSSINCE TRANSPLANTATION Fig. 2 Continued year on year improvement in renal graft survival. Source: United Kingdom Transplant Service, Bristol.
BLOOD REVIEWS
cessfully treated by immunisation with paternal cells, and with leukocytes from third-party donors in some women in studies with relatively small groups of patients. 46,47 The results, although promising are complicated by the need for control groups of adequate size and the exact role of such immunotherapy in recurrent spontaneous abortions remains unclear. Conclusions Blood transfusion may still exert a beneficial effect on renal graft survival. In general, this is now only a small advantage because of cyclosporin and other advances which have enhanced graft survival. Blood transfusion may have a role in specific subsets of recipients, such as those with HLA-DR mismatches or in those patients receiving a second or third graft. The seemingly endless improvements which have led to very good renal graft survival now give rise to difficulties in the dissection of contributions by each of the postulated mechanisms of transfusion-mediated immunosuppression (Fig. 2). There remains the risks of sensitisation and infection and these risks are presently considered by some to outweigh the potential benefits of pretransplant transfusion. However, at present, on the basis of available evidence, we recommend an elective pretransplant transfusion of three units of red cell concentrate. Should anaemia continue to be a problem, then we suggest the use of erythropoietin or if necessary the use of leucocytedepleted blood, although evidence to support the latter course is not yet obtainable. In conclusion, pretransplant transfusion remains a cheap and effective immunosuppressive agent which should remain part of the management of patients for renal transplantation. References 1. Schiller G J, Berkman S A 1989 Haematologic aspects of
renal insufficiency. Blood Reviews 3: 141-146 2. Kissmeyer-Nielsen F, Olsen S, Petersen V P, Fjeldborg 0 1966 Hyperacute rejection of kidney allografts associated with pre-existing humoral antibodies against donor cells. Lancet i: 662-665 3. Opelz G, Terasaki P I 1972 Histocompatibility matching utilizing responsiveness as a new dimension. Transplantation Proceedings 4: 433-437 4. Opelz G, Mickey M R, Terasaki P I 1972 Identification of unresponsive kidney transplant recipients. Lancet i: 868-871 5. Opelz G, Sengar D P S, Mickey M R, Terasaki P I 1973 Effect of blood transfusions on subsequent kidney transplants. Transplantation Proceedings 4 433-437 6. Bucin D, Lindholm T, Low B, Husberg B 1981 Blood transfusion and kidney transplantation. Scandinavian Journal of Urology and Nephrology 64-89 I. Stiller C R, Lockwood B L, Sinclair N R, Ulan R A, Sheppard R R, Sharpe J A, Hayman P 1978 Beneficial effect of operation-day blood transfusions on human renal allograft survival. Lancet i: 169-170 8. Corry R J, West J C, Hunsicker L G, Schabacher B A, Lachenbruch P A 1980 Effect of timing of administration and quantity of blood transfusion on cadaver& renal transplant survival. Transplantation 1980 30: 425-428 9. Qpelz G, Terasaki P I 1981 Importance of preoperative (not peroperative) transfusions for cadaver kidney transplants. Transplantation 31: 106108
257
10. Hourmant M, Soulillou J P, Bui-Quang D 1979 Beneficial effect of blood transfusion. Transplantation 28: 40-43 11. Qpelz G, Terasaki P I 1980 Dominant effect of transfusions on kidney graft survival. Transplantation 29: 153-158 12. Persijn G G, Cohen B, Lansbergen Q, van Rood J J 1979 Retrospective and prospective studies on the effect of blood transfusions in renal transplantation in the Netherlands. Transplantation 2% 396-408 13. Rapaport F T, Dausset J 1984 Facilitation of skin allograft survival by blood leucoyte extracts. Annals of Surgery 199: 79-86 14. Opelz G, Terasaki P I 1978 Improvement of kidney graft survival with increased numbers of blood transfusions. New England Journal of Medicine 299: 799-803 15. Opelz G 1985 Current relevance of the transfusion effect in renal transplantation. Transplantation Proceedings 17: 1015-1022 16. Salvatierra 0 Jr, Vincenti F, Amend W et al 1980 Deliberate donor-specific blood transfusions prior to living related donor transplantation. A new approach. Annals of Surgery 192: 543-552 17. Glass N R, Miller D T, Sollinger H W, Belzer F 0 1985 A four-year experience with donor blood transfusion protocols for living-donor renal transplantation. Transplantation 39: 615-619 18. Sells R A, Scott M H, Prieto M, Bone J M, Evans G M, Millar R, Hillis A N 1989 Early rejection following donorspecific transfusion prior to HLA-mismatched living related renal transplantation. Transplantation Proceedings 21: 1173-1174 19. Opelz G 1989 The role of HLA matching and blood transfusions in the cyclosporine era. Transplantation Proceedings 21: 609-612 20. Iwaki Y, Cecka J M, Terasaki P I 1990 The transfusion effect in cadaver kidney transplants-yes or no. Transplantation 49: 56-59 21. Anonymous 1988 Time to abandon pre-transplant blood transfusion. Lancet i: 567-568 22. D’Apice A J F. Tait B D 1982 An elective transfusion policy: sensitization rates, patient transplantability, and transplant outcome. Transplantation 33: 191-195 23. Singal D P. Joseoh S 1982 Role of blood transfusions on the indiction of ant;bodies against recognition sites on T lymphocytes in renal transplant patients. Human Immunology 4: 93-108 24. Binz H, Wigzell H 1976 Specific transplantation tolerance induced by autoimmunization against the individual’s own, naturally occurring idiotypic, antigen-binding receptors. Journal of Experimental Medicine 144: 1438-1457 25. Keown P A. Descamps B 1979 Improved renal allograft survival after blood transfusion: a non-specific, erythrocytemediated immunoregulatory process? Lancet i: 20-22 26. Watson M A, Briggs J D, Diamandopoulos A A, Hamilton D N H, Dick H M 1979 Endogenous cell-mediated immunity, blood transfusion, and outcome of renal transplantation. Lancet ii: 1323-1326 27. Fischer E, Lenhard V, Seifert P, Kluge A, Johannsen R 1980 Blood transfusion-induced suppression of cellular immunity in man. Human Immunology 3: 187-194 28. Kerman R H, Van Buren C T, Payne W et al 1983 The influence of pretransplant blood transfusions from random donors on immune parameters affecting cadaveric allograft survival. Transplantation 36: 50-54 29. Smith M D, Williams J D, Coles G A, Salaman J R 1983 Blood transfusion, suppressor T cells, and renal transplant survival. Transplantation 36: 647-650 30. Lenhard V, Massen G, Seifert P, Johannsen R, GrosseWilde H 1982 Characterization of transfusion-induced suppressor cells in prospective kidney allograft recipients. Transplantation Proceedings 14: 329-332 31. Lenhard V, Gesma D, Opelz G 1985 Transfusion induced release of prostaglandin E2 and its role in the activation of T suppressor cells. Transplantation Proceedings 17: 2380-2382 32. Jackson V, Tsakus D, Tonner E, Briggs J D, Junor B J R 1985 In vitro prostaglandin E production following multiple blood transfusions in dialysis patients. Transplantation Proceedings 17: 2386-2389 _ 33. Roy R, Lachance J G, Beaudoin R, Grose J H, Noel R 1985 Prostaglandin-dependent suppressor factor induced following
258
34.
35.
36.
31. 38.
39.
40.
BLOOD TRANSFUSION
AND ORGAN TRANSPLANTATION
l-5 blood transfusions: role in kidney graft outcome. Transplantation Proceedings 17: 2382-2385 Anderson C B, Jaffee B M, Gratf R J 1977 Prolongation of murine skin allografts by prostaglandin E 1. Transplantation 23: 444-441 Shelby J, Marushack M M, Nelson E W 1987 Prostaglandin production and suppressor cell induction in transfusioninduced immune suppression. Transplantation 43: 113-l 16 Waymack J P, Gallon L, Barcelli U, Trocki 0, Alexander J W 1987 Effects of blood transfusion on immune function. III. Alterations in macrophage arachidonic acid metabolism. Archives of Surgery 122: 56-60 Van Rood J J 1983 Pretransplant blood transfusion: sure! But how and why? Transplantation Proceedings 15: 915-916 Albert E D, Scholz S, Meixner U, Land W 1981 HLA-A,B matching of pretransplant blood transfusion is associated with poor graft survival. Transplantation Proceedings 13: 175-177 Terasaki P I 1984 The beneficial transfusion effect on kidney graft survival attributed to clonal deletion. Transplantation 37: 119-125 Burrows L, Tartter P 1982 Effect of blood transfusions on colonic malignancy recurrence rate. Lancet ii: 662
41. Salo M 1988 Immunosuppressive effects of blood transfusion in anaesthesia and surgery. Acta Anaethesiologica Scandinavica 39: Supplement 89: 26-34 42. Blumberg N, Heal J M 1989 Transfusion and host defenses against cancer recurrence and infection. Transfusion 29: 236-245 43. Ross W B 1987 Blood transfusion and colorectal cancer. Journal of the Royal College of Surgeons of Edinburgh 32: 197-201 44. Tartter P I 1989 Blood transfusion and postoperative infections. Transfusion 29: 456-459 45. Williams J G, Hughes L E 1989 Effect of perioperative blood transfusion on recurrence of Crohn’s disease. Lancet ii: 131-133 46. Mowbray J F, Gibbings C, Liddell H, Reginald P W, Underwood J L, Beard R W 1985 Controlled trial of treatment of recurrent spontaneous abortion by immunisation with paternal cells. Lancet i: 941-943 41. Unander A M, Lindholm A 1986 Transfusions of leukocyterich erythrocyte concentrates; a successful treatment in selected cases of habitual abortion. American Journal of Obstetrics and Gynecology 154: 516-520
