American Journal of Transplantation 2014; 14: 2903–2905 Wiley Periodicals Inc.
C
Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12973
Case Report
ABO-Compatible Retransplantation After ABOIncompatible Infant Heart Transplantation: Absence of Donor Specific Isohemagglutinins S. Kohler1,*, R. Engmann1, J. Birnbaum1, A. Fuchs1, I. Kaczmarek2, H. Netz1 and R. Kozlik-Feldmann1
first successful pediatric heart transplantation by Bailey in 1985, the number of pediatric heart transplantations has increased considerably, representing 14% of all heart transplants performed in the world in 2011 (1).
1
Department of Pediatric Cardiology and Intensive Care Medicine, Ludwig-Maximilians-University Munich, Munich, Germany 2 Department of Cardiac Surgery, Ludwig-MaximiliansUniversity Munich, Munich, Germany Corresponding author: Sarah Kohler, [email protected]
Implementation of ABO-incompatible (ABOi) pediatric heart transplantation has contributed to significant reduction in the mortality of infants on the waiting list, without increasing the risk of rejection. This has been attributed to the immature and therefore not fully competent immune system in this population group, which results in lower production of isohemagglutinins compared to older children and adults. Serial evaluations of isohemagglutinin titers in infants revealed cases with absence of donor specific antiblood group antibodies. However, it is currently unknown whether continuous exposure to donor antigens is necessary to prevent formation of donor specific isohemagglutinins (DSI) in recipients. We are reporting a case of an infant who underwent ABOi heart transplantation, with no evidence of DSI even 4 years after ABO-compatible retransplantation. Hence, temporary exposure to donor antigens in infants may contribute to permanent absence of donor specific anti-blood group antibodies, suggesting the possibility of induced permanent B cell tolerance. Abbreviations: ABOc, ABO-compatible; ABOi, ABOincompatible; AKI, acute kidney injury; ATG, antithymocyte globulin; DSI, donor specific isohemagglutinins; LVOT, left ventricular outflow tract Received 03 December 2013, revised 21 July 2014 and accepted for publication 03 August 2014
Introduction Heart transplantation is the only available therapy for multiple fatal cardiac diseases during infancy. Since the
The high mortality rate of 58% among infants younger than 6 months, while on the transplant waiting list, lead to the idea of ABO-incompatible (ABOi) heart transplants in 1996. West et al (2) demonstrated this as an alternative for infants in the first 2 years of life, as long as there is a reduced production of isohemagglutinins. The absence of hyperacute rejection was attributed to the immature complement system and insufficient production of isohemagglutinins in early childhood (2). A recent study confirmed that ABOi transplantation does not increase early mortality (3). Followup of children after ABOi heart transplantation showed variability in the development of donor specific isohemagglutinins (DSI). Dipchand et al (4) as well as Conway et al (5) describe in more detail the development of DSI after ABOi heart transplantation. Interestingly, only the minority of the studied patients, about 30%, developed DSI 1.8, and none of them showed normal titers of DSI (5). In some cases, however, persistent absence of DSI was reported, despite normal development of antibodies toward the nondonor blood group. Further studies confirmed an induction of donor-specific B cell tolerance after ABOi heart transplantation in infancy (6,7). Whether transient exposure to donor antigens is sufficient to induce a persistent absence of DSI, however, has not yet been demonstrated. Our center has offered an ABOi heart transplant program since 2004 (8). We report one case of persistent absence of DSI in an ABOi heart transplanted infant 4 years after ABOcompatible (ABOc) retransplantation.
Summary of the Case The girl was born with borderline hypoplastic left heart syndrome and endocardial fibroelastosis. Due to the hypoplastic left ventricle with insufficient growth, as well as persistent high pressure ratios in the pulmonary circulation the infant remained ventilator dependent and was listed for heart transplant at the age of 4 months. Additionally, she developed oliguric acute kidney injury (AKI) despite aggressive treatment with diuretics and subsequently became dialysis dependent while on the 2903
Kohler et al
transplant waiting list. At the age of 7 months, the patient (blood group 0) underwent ABOi heart transplantation (blood group A). She remained dialysis dependent after the transplant. Over the next 4 years the patient developed a progressive hypertrophic cardiomyopathy with left ventricular outflow tract (LVOT) obstruction of unknown origin. An adverse effect of the immunosuppressive therapy with tacrolimus, side effects of steroid therapy or arterial hypertension were considered as possible etiologies of the LVOT obstruction. Neither medical treatment with propranolol, verapamil, change in immunosuppressive regimen, nor surgical resection of the sub valvular aortic stenosis and reconstruction of the mitral valve resulted in improved cardiac function. Due to an increasing LVOT obstruction and mitral regurgitation with refractory pulmonary edema, a retransplantation became necessary. She remained dialysis dependent and therefore became a candidate for a kidney transplant. Almost 6 years after the ABOi (blood group A) heart transplant, she underwent ABOc (blood group 0) heart and kidney transplantation. From an immunologic standpoint, the serum anti-A and antiB titers were both 1:4 prior to the ABOi transplant. During surgery the patient’s blood volume was replaced three times, until antibodies directed toward the donor blood group were no longer detectable. She received induction therapy with rabbit antithymocyte globulin (ATG) and a single dose of daclizumab. The posttransplant immunosuppressive therapy consisted of tacrolimus (after transplant target level 11–13 ng/mL; in the subsequent years reduction to a target level of 7–8 ng/mL), mycophenolic acid and methylprednisolone, which could be discontinued 6 months after transplant. Over the following years several changes in the immunosuppressive regimen became necessary due to severe side effects. After the first 2.5 years under immunosuppressive therapy with tacrolimus and mycophenolic acid, recurrent gastrointestinal side effects prompted a change to tacrolimus and azathioprine. Subsequently due to increasing LVOT obstruction, likely as a side effect of tacrolimus, tacrolimus was switched to cyclosporine A (target level 100–120 ng/mL). After 6 months of treatment with this immunosuppressive therapy, the patient developed sub-clinical acute rejection degree 2R prompting a switch back to tacrolimus and azathioprine. The ABOc (blood group 0) heart retransplantation and primary renal transplantation were performed without induction therapy. The posttransplant immunosuppressive therapy consisted of azathioprine, tacrolimus (after transplant target level 12 ng/mL, in the subsequent years reduction to target level of 6–7 ng/mL) and methylprednisolone. The immunosuppressive therapy with methylprednisolone 0.15 mg/kg was continued given a history of acute renal rejection shortly after transplantation. The patient did not show evidence of hyperacute rejection at any time, neither after the ABOi heart transplantation nor after the ABOc heart and renal transplantation. After ABOi 2904
heart transplantation, the titers of isohemagglutinins were followed and quantified regularly. Additionally, every 1–2 years, the patient underwent a routine cardiac catheterization with myocardial biopsy to evaluate for any early evidence of rejection. The routine cardiac catheterization and myocardial biopsy showed minimal rejection (at most grade 81R) 1 year after ABOi transplantation. An early allograft vasculopathy with no signs of humoral or cellular rejection and grade 2R rejection was seen 3 and 4 years after transplant respectively, but remained sub-clinical. After ABOc transplantation there were no signs of cardiac allograft rejection. The initial posttransplant course was complicated by AKI in the setting of acute renal rejection (grade 2B) but was successfully treated with ATG and high dose steroids. The evaluation of isohemagglutinin titers after ABOi transplantation showed a normal pattern of antibodies toward the nondonor blood group, with maximum anti-B titers of 1:512. In contrast, only minimal anti-A titers were measurable (maximum anti-A1 1:2, anti-A2 1:1). After ABOc retransplantation anti-A titers remained low (maximum anti-A1 and anti-A2 1:4), but a normal anti-B titer (1:128) was detectable.
Discussion Performing ABOi heart transplants in infancy is possible because of low serum anti-A and anti-B titers’ inability to produce isohemagglutinins and a not yet fully competent complement system. As a result, the risk for hyperacute allograft rejection is reduced compared to adult recipients (2). Based on these characteristics of the infantile immune system, it has been shown that ABOi heart transplants in infancy do not need a more aggressive immunosuppressive therapy than ABOc (9,10). Fan et al (7) demonstrated the absence of antibody production toward the donor blood group with otherwise normal antibody production toward the nondonor blood group after ABOi heart transplantation in infancy. Graft accommodation is a phenomenon, for example described in ABOi kidney transplants in adults, where normal titers of isohemagglutinins against the donor blood group are detected without a sign of rejection and sometimes also without evidence of deposition of donor blood group antibodies in the graft (11–13). After ABOi heart transplantation in infancy, reduced serum antibody titers toward the donor blood group may represent a sign of induced B cell tolerance against donor blood group antigens (7). However, not all patients after ABOi transplantation in childhood show absence of DSI (4,5). Conway et al described a production of DSI with a titer of greater than 1:8 in 27% of cases. Older age at the time of transplantation, pretransplant anti-B titer greater than 1:8 and HLA sensitization have been identified as risk factors for the production of DSI (5). In our case described above, the patient would be classified as low risk for the development of DSI according to Conway American Journal of Transplantation 2014; 14: 2903–2905
Absence of Donor Specific Isohemagglutinins
et al (5). The infant underwent ABOi heart transplantation at the young age of 7 months, had no HLA sensitization and a low anti-B titer of 1:4 prior transplantation (5). The patient continued to lack DSI 4 years after ABOc retransplantation. The multicenter study by Urschel et al (9) includes a 7-yearold girl who underwent second ABOi heart transplantation. The donor of first and second allograft had the same blood group. Despite such a late ABOi transplantation the recipient showed no signs of hyperacute rejection. This case suggests the persistence of the changed isohemagglutinin response (9). Whether the persistence of the donor antigen is necessary for the lack of DSI production is unknown at this time. Animal models have demonstrated that induced graft tolerance with persistence of an alloantigen, remain indefinitely. However, after removal of the graft, the induced tolerance was lost (14,15). In our case, 4 years after ABOc retransplantation, the patient still showed absence of DSI, possibly result of induced B cell tolerance. Nevertheless the last evaluation of the anti-A isohemagglutinin showed a rise to 1:4. Whether this result reflects a trend or is just an outlier needs to be evaluated over the next years. However despite this rise of the anti-A isohemagglutinin titer there is still no normal production of anti-A isohemagglutinin while normal anti-B isohemagglutinin production with titers of 1:128. An altered immune response was also described in children after pneumococcal conjugate vaccination. Children colonized with pneumococcus prior to the vaccination showed a significant lower response to the immunization (16). Urschel et al (9) interpreted these findings as a possible sign of a down-regulated B cell response because of contact with a large amount of T-independent antigens. The patient described in our case received ABOc (blood group 0) retransplantation of the heart and an ABOc (blood group 0) kidney transplant simultaneously. In comparison to ABOi heart transplantation, accommodation is more often seen after ABOi renal transplants. To what extend a combined ABOi heart and kidney transplantation influenced the development of donor blood group tolerance is unknown. Further studies are necessary. With the case mentioned above we could provide some evidence that temporary antigen presentation can cause persistent absence of DSI, probably as a sign of induced B cell tolerance.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
American Journal of Transplantation 2014; 14: 2903–2905
References 1. Dipchand AI, Kirk R, Edwards LB, et al. The registry of the international society for heart and lung transplantation: Sixteenth official pediatric heart transplantation report-2013; focus theme: Age. J Heart Lung Transplant 2013; 32: 979–988. 2. West LJ, Pollock-Barziv SM, Dipchand AI, et al. ABO-incompatible heart transplantation in infants. N Engl J Med 2001; 344: 793–800. 3. Henderson HT, Canter CE, Mahle WT, et al. AB0-incompatible heart transplantation: Analysis of the Pediatric Heart Transplant Study (PHTS) database. J Heart Lung Transplant 2012; 31: 173– 179. 4. Dipchand AI, Pollock BarZiv SM, Manlhiot C, West LJ, VanderVliet M, McCrindle BW. Equivalent outcomes for pediatric heart transplantation recipients: ABO-blood group incompatible versus ABO-compatible. Am J Transplant 2010; 10: 389–397. 5. Conway J, Manlhiot C, Allain-Rooney T, McCrindle BW, Lau W, Dipchand AI. Development of donor-specific isohemagglutinins following pediatric ABO-incompatible heart transplantation. Am J Transplant 2012; 12: 888–895. 6. Urschel S, Campbell PM, Meyer SR, et al. Absence of donorspecific anti-HLA antibodies after ABO-incompatible heart transplantation in infancy: Altered immunity or age? Am J Transplant 2010; 10: 149–156. 7. Fan X, Ang A, Pollock-Barziv SM, et al. Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation. Nat Med 2004; 10: 1227–1233. 8. Schmoeckel M, Da¨britz SH, Kozlik-Feldmann R, et al. Successful AB0-incompatible heart transplantation in two infants. Transpl Int 2005; 18: 1210–1214. 9. Urschel S, Larsen IM, Kirk R, et al. ABO-incompatible heart transplantation in early childhood: An international multicenter study of clinical experiences and limits. J Heart Lung Transplant 2013; 32: 285–292. 10. Roche SL, Burch M, O’Sullivan J, et al. Multicenter experience of ABO-incompatible pediatric cardiac transplantation. Am J Transplant 2008; 8: 208–215. 11. Lynch RJ, Platt JL. Accommodation in organ transplantation. Curr Opin Organ Transplant 2008; 13: 165–170. 12. Bannett AD, McAlack RF, Morris M, Chopek MW, Platt JL. ABO incompatible renal transplantation: A qualitative analysis of native endothelial tissue ABO antigens after transplantation. Transplant Proc 1989; 21: 783–785. 13. Chopek MW, Simmons RL, Platt JL. ABO-incompatible kidney transplantation: Initial immunopathologic evaluation. Transplant Proc 1987; 19: 4553–4557. 14. Hamano K, Rawsthorne MA, Bushell AR, Morris PJ, Wood KJ. Evidence that the continued presence of the organ graft and not peripheral donor microchimerism is essential for maintenance of tolerance to alloantigen in vivo in anti-CD4 treated recipients. Transplantation 1996; 62: 856–860. 15. Morecki S, Leshem B, Eid A, Slavin S. Alloantigen persistence in induction and maintenance of transplantation tolerance. J Exp Med 1987; 165: 1468–1480. 16. Dagan R1, Givon-Lavi N, Greenberg D, Fritzell B, Siegrist CA. Nasopharyngeal carriage of Streptococcus pneumoniae shortly before vaccination with a pneumococcal conjugate vaccine causes serotype-specific hyporesponsiveness in early infancy. J Infect Dis 2010; 201: 1570–1579.
2905
C
Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12973
Case Report
ABO-Compatible Retransplantation After ABOIncompatible Infant Heart Transplantation: Absence of Donor Specific Isohemagglutinins S. Kohler1,*, R. Engmann1, J. Birnbaum1, A. Fuchs1, I. Kaczmarek2, H. Netz1 and R. Kozlik-Feldmann1
first successful pediatric heart transplantation by Bailey in 1985, the number of pediatric heart transplantations has increased considerably, representing 14% of all heart transplants performed in the world in 2011 (1).
1
Department of Pediatric Cardiology and Intensive Care Medicine, Ludwig-Maximilians-University Munich, Munich, Germany 2 Department of Cardiac Surgery, Ludwig-MaximiliansUniversity Munich, Munich, Germany Corresponding author: Sarah Kohler, [email protected]
Implementation of ABO-incompatible (ABOi) pediatric heart transplantation has contributed to significant reduction in the mortality of infants on the waiting list, without increasing the risk of rejection. This has been attributed to the immature and therefore not fully competent immune system in this population group, which results in lower production of isohemagglutinins compared to older children and adults. Serial evaluations of isohemagglutinin titers in infants revealed cases with absence of donor specific antiblood group antibodies. However, it is currently unknown whether continuous exposure to donor antigens is necessary to prevent formation of donor specific isohemagglutinins (DSI) in recipients. We are reporting a case of an infant who underwent ABOi heart transplantation, with no evidence of DSI even 4 years after ABO-compatible retransplantation. Hence, temporary exposure to donor antigens in infants may contribute to permanent absence of donor specific anti-blood group antibodies, suggesting the possibility of induced permanent B cell tolerance. Abbreviations: ABOc, ABO-compatible; ABOi, ABOincompatible; AKI, acute kidney injury; ATG, antithymocyte globulin; DSI, donor specific isohemagglutinins; LVOT, left ventricular outflow tract Received 03 December 2013, revised 21 July 2014 and accepted for publication 03 August 2014
Introduction Heart transplantation is the only available therapy for multiple fatal cardiac diseases during infancy. Since the
The high mortality rate of 58% among infants younger than 6 months, while on the transplant waiting list, lead to the idea of ABO-incompatible (ABOi) heart transplants in 1996. West et al (2) demonstrated this as an alternative for infants in the first 2 years of life, as long as there is a reduced production of isohemagglutinins. The absence of hyperacute rejection was attributed to the immature complement system and insufficient production of isohemagglutinins in early childhood (2). A recent study confirmed that ABOi transplantation does not increase early mortality (3). Followup of children after ABOi heart transplantation showed variability in the development of donor specific isohemagglutinins (DSI). Dipchand et al (4) as well as Conway et al (5) describe in more detail the development of DSI after ABOi heart transplantation. Interestingly, only the minority of the studied patients, about 30%, developed DSI 1.8, and none of them showed normal titers of DSI (5). In some cases, however, persistent absence of DSI was reported, despite normal development of antibodies toward the nondonor blood group. Further studies confirmed an induction of donor-specific B cell tolerance after ABOi heart transplantation in infancy (6,7). Whether transient exposure to donor antigens is sufficient to induce a persistent absence of DSI, however, has not yet been demonstrated. Our center has offered an ABOi heart transplant program since 2004 (8). We report one case of persistent absence of DSI in an ABOi heart transplanted infant 4 years after ABOcompatible (ABOc) retransplantation.
Summary of the Case The girl was born with borderline hypoplastic left heart syndrome and endocardial fibroelastosis. Due to the hypoplastic left ventricle with insufficient growth, as well as persistent high pressure ratios in the pulmonary circulation the infant remained ventilator dependent and was listed for heart transplant at the age of 4 months. Additionally, she developed oliguric acute kidney injury (AKI) despite aggressive treatment with diuretics and subsequently became dialysis dependent while on the 2903
Kohler et al
transplant waiting list. At the age of 7 months, the patient (blood group 0) underwent ABOi heart transplantation (blood group A). She remained dialysis dependent after the transplant. Over the next 4 years the patient developed a progressive hypertrophic cardiomyopathy with left ventricular outflow tract (LVOT) obstruction of unknown origin. An adverse effect of the immunosuppressive therapy with tacrolimus, side effects of steroid therapy or arterial hypertension were considered as possible etiologies of the LVOT obstruction. Neither medical treatment with propranolol, verapamil, change in immunosuppressive regimen, nor surgical resection of the sub valvular aortic stenosis and reconstruction of the mitral valve resulted in improved cardiac function. Due to an increasing LVOT obstruction and mitral regurgitation with refractory pulmonary edema, a retransplantation became necessary. She remained dialysis dependent and therefore became a candidate for a kidney transplant. Almost 6 years after the ABOi (blood group A) heart transplant, she underwent ABOc (blood group 0) heart and kidney transplantation. From an immunologic standpoint, the serum anti-A and antiB titers were both 1:4 prior to the ABOi transplant. During surgery the patient’s blood volume was replaced three times, until antibodies directed toward the donor blood group were no longer detectable. She received induction therapy with rabbit antithymocyte globulin (ATG) and a single dose of daclizumab. The posttransplant immunosuppressive therapy consisted of tacrolimus (after transplant target level 11–13 ng/mL; in the subsequent years reduction to a target level of 7–8 ng/mL), mycophenolic acid and methylprednisolone, which could be discontinued 6 months after transplant. Over the following years several changes in the immunosuppressive regimen became necessary due to severe side effects. After the first 2.5 years under immunosuppressive therapy with tacrolimus and mycophenolic acid, recurrent gastrointestinal side effects prompted a change to tacrolimus and azathioprine. Subsequently due to increasing LVOT obstruction, likely as a side effect of tacrolimus, tacrolimus was switched to cyclosporine A (target level 100–120 ng/mL). After 6 months of treatment with this immunosuppressive therapy, the patient developed sub-clinical acute rejection degree 2R prompting a switch back to tacrolimus and azathioprine. The ABOc (blood group 0) heart retransplantation and primary renal transplantation were performed without induction therapy. The posttransplant immunosuppressive therapy consisted of azathioprine, tacrolimus (after transplant target level 12 ng/mL, in the subsequent years reduction to target level of 6–7 ng/mL) and methylprednisolone. The immunosuppressive therapy with methylprednisolone 0.15 mg/kg was continued given a history of acute renal rejection shortly after transplantation. The patient did not show evidence of hyperacute rejection at any time, neither after the ABOi heart transplantation nor after the ABOc heart and renal transplantation. After ABOi 2904
heart transplantation, the titers of isohemagglutinins were followed and quantified regularly. Additionally, every 1–2 years, the patient underwent a routine cardiac catheterization with myocardial biopsy to evaluate for any early evidence of rejection. The routine cardiac catheterization and myocardial biopsy showed minimal rejection (at most grade 81R) 1 year after ABOi transplantation. An early allograft vasculopathy with no signs of humoral or cellular rejection and grade 2R rejection was seen 3 and 4 years after transplant respectively, but remained sub-clinical. After ABOc transplantation there were no signs of cardiac allograft rejection. The initial posttransplant course was complicated by AKI in the setting of acute renal rejection (grade 2B) but was successfully treated with ATG and high dose steroids. The evaluation of isohemagglutinin titers after ABOi transplantation showed a normal pattern of antibodies toward the nondonor blood group, with maximum anti-B titers of 1:512. In contrast, only minimal anti-A titers were measurable (maximum anti-A1 1:2, anti-A2 1:1). After ABOc retransplantation anti-A titers remained low (maximum anti-A1 and anti-A2 1:4), but a normal anti-B titer (1:128) was detectable.
Discussion Performing ABOi heart transplants in infancy is possible because of low serum anti-A and anti-B titers’ inability to produce isohemagglutinins and a not yet fully competent complement system. As a result, the risk for hyperacute allograft rejection is reduced compared to adult recipients (2). Based on these characteristics of the infantile immune system, it has been shown that ABOi heart transplants in infancy do not need a more aggressive immunosuppressive therapy than ABOc (9,10). Fan et al (7) demonstrated the absence of antibody production toward the donor blood group with otherwise normal antibody production toward the nondonor blood group after ABOi heart transplantation in infancy. Graft accommodation is a phenomenon, for example described in ABOi kidney transplants in adults, where normal titers of isohemagglutinins against the donor blood group are detected without a sign of rejection and sometimes also without evidence of deposition of donor blood group antibodies in the graft (11–13). After ABOi heart transplantation in infancy, reduced serum antibody titers toward the donor blood group may represent a sign of induced B cell tolerance against donor blood group antigens (7). However, not all patients after ABOi transplantation in childhood show absence of DSI (4,5). Conway et al described a production of DSI with a titer of greater than 1:8 in 27% of cases. Older age at the time of transplantation, pretransplant anti-B titer greater than 1:8 and HLA sensitization have been identified as risk factors for the production of DSI (5). In our case described above, the patient would be classified as low risk for the development of DSI according to Conway American Journal of Transplantation 2014; 14: 2903–2905
Absence of Donor Specific Isohemagglutinins
et al (5). The infant underwent ABOi heart transplantation at the young age of 7 months, had no HLA sensitization and a low anti-B titer of 1:4 prior transplantation (5). The patient continued to lack DSI 4 years after ABOc retransplantation. The multicenter study by Urschel et al (9) includes a 7-yearold girl who underwent second ABOi heart transplantation. The donor of first and second allograft had the same blood group. Despite such a late ABOi transplantation the recipient showed no signs of hyperacute rejection. This case suggests the persistence of the changed isohemagglutinin response (9). Whether the persistence of the donor antigen is necessary for the lack of DSI production is unknown at this time. Animal models have demonstrated that induced graft tolerance with persistence of an alloantigen, remain indefinitely. However, after removal of the graft, the induced tolerance was lost (14,15). In our case, 4 years after ABOc retransplantation, the patient still showed absence of DSI, possibly result of induced B cell tolerance. Nevertheless the last evaluation of the anti-A isohemagglutinin showed a rise to 1:4. Whether this result reflects a trend or is just an outlier needs to be evaluated over the next years. However despite this rise of the anti-A isohemagglutinin titer there is still no normal production of anti-A isohemagglutinin while normal anti-B isohemagglutinin production with titers of 1:128. An altered immune response was also described in children after pneumococcal conjugate vaccination. Children colonized with pneumococcus prior to the vaccination showed a significant lower response to the immunization (16). Urschel et al (9) interpreted these findings as a possible sign of a down-regulated B cell response because of contact with a large amount of T-independent antigens. The patient described in our case received ABOc (blood group 0) retransplantation of the heart and an ABOc (blood group 0) kidney transplant simultaneously. In comparison to ABOi heart transplantation, accommodation is more often seen after ABOi renal transplants. To what extend a combined ABOi heart and kidney transplantation influenced the development of donor blood group tolerance is unknown. Further studies are necessary. With the case mentioned above we could provide some evidence that temporary antigen presentation can cause persistent absence of DSI, probably as a sign of induced B cell tolerance.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
American Journal of Transplantation 2014; 14: 2903–2905
References 1. Dipchand AI, Kirk R, Edwards LB, et al. The registry of the international society for heart and lung transplantation: Sixteenth official pediatric heart transplantation report-2013; focus theme: Age. J Heart Lung Transplant 2013; 32: 979–988. 2. West LJ, Pollock-Barziv SM, Dipchand AI, et al. ABO-incompatible heart transplantation in infants. N Engl J Med 2001; 344: 793–800. 3. Henderson HT, Canter CE, Mahle WT, et al. AB0-incompatible heart transplantation: Analysis of the Pediatric Heart Transplant Study (PHTS) database. J Heart Lung Transplant 2012; 31: 173– 179. 4. Dipchand AI, Pollock BarZiv SM, Manlhiot C, West LJ, VanderVliet M, McCrindle BW. Equivalent outcomes for pediatric heart transplantation recipients: ABO-blood group incompatible versus ABO-compatible. Am J Transplant 2010; 10: 389–397. 5. Conway J, Manlhiot C, Allain-Rooney T, McCrindle BW, Lau W, Dipchand AI. Development of donor-specific isohemagglutinins following pediatric ABO-incompatible heart transplantation. Am J Transplant 2012; 12: 888–895. 6. Urschel S, Campbell PM, Meyer SR, et al. Absence of donorspecific anti-HLA antibodies after ABO-incompatible heart transplantation in infancy: Altered immunity or age? Am J Transplant 2010; 10: 149–156. 7. Fan X, Ang A, Pollock-Barziv SM, et al. Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation. Nat Med 2004; 10: 1227–1233. 8. Schmoeckel M, Da¨britz SH, Kozlik-Feldmann R, et al. Successful AB0-incompatible heart transplantation in two infants. Transpl Int 2005; 18: 1210–1214. 9. Urschel S, Larsen IM, Kirk R, et al. ABO-incompatible heart transplantation in early childhood: An international multicenter study of clinical experiences and limits. J Heart Lung Transplant 2013; 32: 285–292. 10. Roche SL, Burch M, O’Sullivan J, et al. Multicenter experience of ABO-incompatible pediatric cardiac transplantation. Am J Transplant 2008; 8: 208–215. 11. Lynch RJ, Platt JL. Accommodation in organ transplantation. Curr Opin Organ Transplant 2008; 13: 165–170. 12. Bannett AD, McAlack RF, Morris M, Chopek MW, Platt JL. ABO incompatible renal transplantation: A qualitative analysis of native endothelial tissue ABO antigens after transplantation. Transplant Proc 1989; 21: 783–785. 13. Chopek MW, Simmons RL, Platt JL. ABO-incompatible kidney transplantation: Initial immunopathologic evaluation. Transplant Proc 1987; 19: 4553–4557. 14. Hamano K, Rawsthorne MA, Bushell AR, Morris PJ, Wood KJ. Evidence that the continued presence of the organ graft and not peripheral donor microchimerism is essential for maintenance of tolerance to alloantigen in vivo in anti-CD4 treated recipients. Transplantation 1996; 62: 856–860. 15. Morecki S, Leshem B, Eid A, Slavin S. Alloantigen persistence in induction and maintenance of transplantation tolerance. J Exp Med 1987; 165: 1468–1480. 16. Dagan R1, Givon-Lavi N, Greenberg D, Fritzell B, Siegrist CA. Nasopharyngeal carriage of Streptococcus pneumoniae shortly before vaccination with a pneumococcal conjugate vaccine causes serotype-specific hyporesponsiveness in early infancy. J Infect Dis 2010; 201: 1570–1579.
2905
