617
of von Willebrand factor. Annu Rev Cell Biol 1990, 6: 217-45. 5 Editorial. Factor VIII related antigen and vasculitis. Lancet 1988; i: 1203-04. o MeKenna K, McGrann S, Blann A, Allen J. An investigation into the acute vascular effects of riveting. Br JIndust Med (in press). 4
Wagner DD. Cell biology
Hepatitis A vaccination SIR,-As Dr Black and colleagues (July 25, p 244) state, a decision to vaccinate a traveller should be based on risk and costbenefit analysis. We agree, but would raise some additional points. With respect to the risk of hepatitis A virus (HAV) infection for travellers we refer to previous reports,l in which an incidence rate for unprotected travellers of 3 per 1000 per month of stay in developing countries is given. Clinical HAV infection in an individual leads to an average incapacity for work of 1 month and several direct and indirect costs, and also has a case fatality rate of 0 02 to 1.5%.2 Some important variables in cost-benefit analysis of hepatitis A vaccination for travellers additional to those enumerated by Black et al need to be considered. They are: the prevalence of naturally acquired HAV antibodies; the possibility of screening for these antibodies and of vaccinating only susceptible individuals; travelling behaviour (including frequency of travel); and the duration of protection by vaccination. We would also comment on the statement that 5 million travellers would need to be vaccinated annually. To avoid the waste of expensive vaccine, travellers to high endemic countries could be screened for the presence of HAV antibodies and only susceptible travellers vaccinated. Since more and more individuals can be regarded as frequent travellers, the advantage of the duration of the protection offered by the vaccine has to be compared with other alternatives such as doing nothing or passive immunisation. Finally, we feel that applying the do-nothing strategy to all 5 million travellers is as foolish as giving routine vaccination to all 5 million. Our calculations3 suggest that screening, for example, a 40-year-old traveller for the presence of HAV antibodies and vaccinating only if he is susceptible is a relevant alternative to doing nothing if the attack rate in susceptibles staying abroad is sufficiently high, or if the individual travels regularly. We fully agree that the validity of nationwide recommendations for HAV prevention in travellers will increase as more reliable data concerning region-specific infection rates, age-specific prevalence of HAV antibodies, age-specific morbidity, and travelling behaviour become available. However, it should be recognised that traveller groups can already be identified as being at risk from HAV infection while abroad and that active immunisation, although expensive, competes with the do-nothing approach and with the present passive immunisation strategy, which is a costly and short-term solution. Department of Epidemiology and Community Medicine, University of Antwerp, 2610 Antwerp, Belgium
PIERRE VAN DAMME GUY TORMANS EDDY VAN DOORSLAER
1 Steffen R The epidemiological basis for the practice of travel medicine. Proceedings, 2nd Conference on International Travel Medicine; 1991 May 9-12; Atlanta. 2 Anon. Clinical hepatitis A. Laboratory reports 1980-88. Communic Dis Rep 1990;
89/46.
G, Van Damme P, Van Doorslaer E. Cost-effectiveness analysis hepatitis A vaccination in travellers Vaccine (in press).
3 Tormans
step in induction of long-term graft acceptance. That persistent chimerism may be necessary for maintenance of unresponsiveness to allografts in animal models of tolerance is not a new concept. However, Starzl’s striking observation that dendritic cells of donor origin can be found in the lymphoid organs, skin, heart, or other tissues of human recipients even years after transplantation is original and important. Although the precise mechanisms by which the tolerogenic effects are mediated in this system remain to be established, one possibility proposed by Starzl et al is that the presence of large numbers of donor-derived lymphoid elements in the allograft and their migration to the recipient promotes the mutual proliferation and subsequent elimination of host-versusgraft and graft-versus-host specific populations. Although this process may indeed by important, an additional and perhaps equally salient possibility is that the migration of donor-derived lymphoid cells from the graft leads to establishment of haemopoietic microchimerism in the thymus of the recipient. This lymphoid organ would be one host site to which the migration of donor lymphoid cells would seem likely. Because of the thymus’ unique role in induction of self-tolerance, such a process might ensure that T-cell populations maturing in the chimeric thymus are exposed to donor alloantigens, thus becoming specifically tolerant to them. In support of this hypothesis experimental models in which tolerance is achieved by the administration of allogeneic haemopoietic cells to neonatal recipients or to heavily immunosuppressed adult ones have shown that the establishment of unresponsiveness necessitates the continued presence of at least small numbers of donor-derived cells in the thymus. There may be a relation between Starzl’s findings and those of our group that tolerance can be obtained by implanting cells of donor origin into the thymus of a prospective allograft recipient. After discussion with Starzl we agree that the two sets of findings could be related since chimerism is a central consideration in both. Direct inoculation of donor cells into the thymus could be especially effective for induction of allograft tolerance since it is such an efficient method of promoting lasting thymic microchimerism. In our studies, intrathymic inoculation of allogeneic pancreatic islets,1,2 bone marrow,3 or splenocytes’ into rats immunosuppressed with only one dose of antilymphocyte serum resulted in persistence of the injectate in the thymus. Thus the thymus seems to be an immunologically privileged site. More importantly, this treatment rendered recipients specifically and permanently unresponsive to donor-strain islets transplanted extrathymically or to cardiac allografts. No additional immunosuppression was needed to protect these allografts, which were used as a test of the tolerant state. We found that this protocol would produce neither chimerism nor unresponsiveness if the conditioning inoculum of donor cells was introduced systemically (intravenously) or into an extrathymic transplant site such as the renal subcapsule or testicle. In similar experiments, Remuzzi et al6 showed that rats conditioned with intrathymic injections of another tissue (isolated renal glomeruli) could not reject subsequent transplanted donor-strain renal allografts. These findings underscore the particular importance of thymic chimerism in the development of longlasting and stable unresponsiveness, and may be of critical relevance to the model proposed by Starzl et al.
of
Department of Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
ANDREW M. POSSELT ALI NAJI CLYDE F. BARKER
Microchimerism of the thymus and graft
acceptance SIR,-Dr Starzl and colleagues (June 27, p 1579) report the intriguing finding that patients with established liver allografts harbour donor-derived, class II + lymphoid cells in their extrahepatic tissues, and suggest that the development of this systemic chimeric state is in part responsible for the resistance of liver allografts to rejection as well as the ability of experimental liver allografts to promote specific unresponsiveness to subsequent transplants of non-hepatic tissue from the same donor strain. They suggest that migration of passenger leucocytes (especially dendritic cells, from liver, intestinal, or even kidney allografts and the persistence of these donor cells in host tissues may be an important
1 Posselt
AM, Barker CF, Tomaszewski JE, Markmann JF, Choti MA, Naji A. Induction of donor-specific unresponsiveness by intrathymic islet transplantation. Science 1990; 249: 1293. 2. Posselt AM, Naji A, Roark J, Markmann JF, Barker CF. Intrathymic islet transplantanon in the spontaneously diabetic BB rat. Ann Surg 1991; 214: 363. 3 Posselt AM, Odonco JS, Barker CF, Naji A Promotion of pancreatic islet allograft survival by intrathymic transplantation of bone marrow. Diabetes 1992; 41: 771. 4. Odorico JS, Posselt AM, Naji A, Markmann JF, Barker CF. Promotion of rat cardiac allograft survival by intrathymic inoculation of donor splenocytes. Transplantation (in press) JS, Barker CF, Posselt AM, Naji A. Induction of donor specific tolerance to rat cardiac allografts by intrathymic inoculation of bone marrow. Surgery (in press). Remuzzi G, Rossini M, Imberti O, Perico N Kidney graft survival in rats without immunosuppression after intrathymic glomerular transplantation. Lancet 1991;
5. Odonco 6.
337: 750
of von Willebrand factor. Annu Rev Cell Biol 1990, 6: 217-45. 5 Editorial. Factor VIII related antigen and vasculitis. Lancet 1988; i: 1203-04. o MeKenna K, McGrann S, Blann A, Allen J. An investigation into the acute vascular effects of riveting. Br JIndust Med (in press). 4
Wagner DD. Cell biology
Hepatitis A vaccination SIR,-As Dr Black and colleagues (July 25, p 244) state, a decision to vaccinate a traveller should be based on risk and costbenefit analysis. We agree, but would raise some additional points. With respect to the risk of hepatitis A virus (HAV) infection for travellers we refer to previous reports,l in which an incidence rate for unprotected travellers of 3 per 1000 per month of stay in developing countries is given. Clinical HAV infection in an individual leads to an average incapacity for work of 1 month and several direct and indirect costs, and also has a case fatality rate of 0 02 to 1.5%.2 Some important variables in cost-benefit analysis of hepatitis A vaccination for travellers additional to those enumerated by Black et al need to be considered. They are: the prevalence of naturally acquired HAV antibodies; the possibility of screening for these antibodies and of vaccinating only susceptible individuals; travelling behaviour (including frequency of travel); and the duration of protection by vaccination. We would also comment on the statement that 5 million travellers would need to be vaccinated annually. To avoid the waste of expensive vaccine, travellers to high endemic countries could be screened for the presence of HAV antibodies and only susceptible travellers vaccinated. Since more and more individuals can be regarded as frequent travellers, the advantage of the duration of the protection offered by the vaccine has to be compared with other alternatives such as doing nothing or passive immunisation. Finally, we feel that applying the do-nothing strategy to all 5 million travellers is as foolish as giving routine vaccination to all 5 million. Our calculations3 suggest that screening, for example, a 40-year-old traveller for the presence of HAV antibodies and vaccinating only if he is susceptible is a relevant alternative to doing nothing if the attack rate in susceptibles staying abroad is sufficiently high, or if the individual travels regularly. We fully agree that the validity of nationwide recommendations for HAV prevention in travellers will increase as more reliable data concerning region-specific infection rates, age-specific prevalence of HAV antibodies, age-specific morbidity, and travelling behaviour become available. However, it should be recognised that traveller groups can already be identified as being at risk from HAV infection while abroad and that active immunisation, although expensive, competes with the do-nothing approach and with the present passive immunisation strategy, which is a costly and short-term solution. Department of Epidemiology and Community Medicine, University of Antwerp, 2610 Antwerp, Belgium
PIERRE VAN DAMME GUY TORMANS EDDY VAN DOORSLAER
1 Steffen R The epidemiological basis for the practice of travel medicine. Proceedings, 2nd Conference on International Travel Medicine; 1991 May 9-12; Atlanta. 2 Anon. Clinical hepatitis A. Laboratory reports 1980-88. Communic Dis Rep 1990;
89/46.
G, Van Damme P, Van Doorslaer E. Cost-effectiveness analysis hepatitis A vaccination in travellers Vaccine (in press).
3 Tormans
step in induction of long-term graft acceptance. That persistent chimerism may be necessary for maintenance of unresponsiveness to allografts in animal models of tolerance is not a new concept. However, Starzl’s striking observation that dendritic cells of donor origin can be found in the lymphoid organs, skin, heart, or other tissues of human recipients even years after transplantation is original and important. Although the precise mechanisms by which the tolerogenic effects are mediated in this system remain to be established, one possibility proposed by Starzl et al is that the presence of large numbers of donor-derived lymphoid elements in the allograft and their migration to the recipient promotes the mutual proliferation and subsequent elimination of host-versusgraft and graft-versus-host specific populations. Although this process may indeed by important, an additional and perhaps equally salient possibility is that the migration of donor-derived lymphoid cells from the graft leads to establishment of haemopoietic microchimerism in the thymus of the recipient. This lymphoid organ would be one host site to which the migration of donor lymphoid cells would seem likely. Because of the thymus’ unique role in induction of self-tolerance, such a process might ensure that T-cell populations maturing in the chimeric thymus are exposed to donor alloantigens, thus becoming specifically tolerant to them. In support of this hypothesis experimental models in which tolerance is achieved by the administration of allogeneic haemopoietic cells to neonatal recipients or to heavily immunosuppressed adult ones have shown that the establishment of unresponsiveness necessitates the continued presence of at least small numbers of donor-derived cells in the thymus. There may be a relation between Starzl’s findings and those of our group that tolerance can be obtained by implanting cells of donor origin into the thymus of a prospective allograft recipient. After discussion with Starzl we agree that the two sets of findings could be related since chimerism is a central consideration in both. Direct inoculation of donor cells into the thymus could be especially effective for induction of allograft tolerance since it is such an efficient method of promoting lasting thymic microchimerism. In our studies, intrathymic inoculation of allogeneic pancreatic islets,1,2 bone marrow,3 or splenocytes’ into rats immunosuppressed with only one dose of antilymphocyte serum resulted in persistence of the injectate in the thymus. Thus the thymus seems to be an immunologically privileged site. More importantly, this treatment rendered recipients specifically and permanently unresponsive to donor-strain islets transplanted extrathymically or to cardiac allografts. No additional immunosuppression was needed to protect these allografts, which were used as a test of the tolerant state. We found that this protocol would produce neither chimerism nor unresponsiveness if the conditioning inoculum of donor cells was introduced systemically (intravenously) or into an extrathymic transplant site such as the renal subcapsule or testicle. In similar experiments, Remuzzi et al6 showed that rats conditioned with intrathymic injections of another tissue (isolated renal glomeruli) could not reject subsequent transplanted donor-strain renal allografts. These findings underscore the particular importance of thymic chimerism in the development of longlasting and stable unresponsiveness, and may be of critical relevance to the model proposed by Starzl et al.
of
Department of Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
ANDREW M. POSSELT ALI NAJI CLYDE F. BARKER
Microchimerism of the thymus and graft
acceptance SIR,-Dr Starzl and colleagues (June 27, p 1579) report the intriguing finding that patients with established liver allografts harbour donor-derived, class II + lymphoid cells in their extrahepatic tissues, and suggest that the development of this systemic chimeric state is in part responsible for the resistance of liver allografts to rejection as well as the ability of experimental liver allografts to promote specific unresponsiveness to subsequent transplants of non-hepatic tissue from the same donor strain. They suggest that migration of passenger leucocytes (especially dendritic cells, from liver, intestinal, or even kidney allografts and the persistence of these donor cells in host tissues may be an important
1 Posselt
AM, Barker CF, Tomaszewski JE, Markmann JF, Choti MA, Naji A. Induction of donor-specific unresponsiveness by intrathymic islet transplantation. Science 1990; 249: 1293. 2. Posselt AM, Naji A, Roark J, Markmann JF, Barker CF. Intrathymic islet transplantanon in the spontaneously diabetic BB rat. Ann Surg 1991; 214: 363. 3 Posselt AM, Odonco JS, Barker CF, Naji A Promotion of pancreatic islet allograft survival by intrathymic transplantation of bone marrow. Diabetes 1992; 41: 771. 4. Odorico JS, Posselt AM, Naji A, Markmann JF, Barker CF. Promotion of rat cardiac allograft survival by intrathymic inoculation of donor splenocytes. Transplantation (in press) JS, Barker CF, Posselt AM, Naji A. Induction of donor specific tolerance to rat cardiac allografts by intrathymic inoculation of bone marrow. Surgery (in press). Remuzzi G, Rossini M, Imberti O, Perico N Kidney graft survival in rats without immunosuppression after intrathymic glomerular transplantation. Lancet 1991;
5. Odonco 6.
337: 750
