T Koshiba

Liver transplantation from an identical twin without immunosuppression, with early recurrence of hepatitis C.

Hepatitis C virus reinfection after liver transplantation is universal and more severe than in nontransplant patients. Rejection episodes and immunosuppressive agents are considered risk factors for deterioration of recurrent hepatitis C. We report 2 cases of living donor liver transplantation for patients with hepatitis C‐related cirrhosis who received right‐lobe grafts from an identical twin. Thanks to genetic identity, no immunosuppressive drugs were administered during or after transplantation without rejection. Hepatitis C virus RNA kinetics showed a rapid increase following transplantation and liver biopsies 1 month after transplantation showed acute lobular hepatitis in both cases. Antiviral therapy using interferon α and ribavirin was started immediately, and both cases showed virological and histological response. In conclusion, avoidance of immunosuppression did not delay hepatitis C recurrence following transplantation, while early antiviral therapy without risk of rejection or immunosuppression led to successful viral eradication.

Combined use of FTY720 and cyclosporine a prevents chronic allograft vasculopathy

FTY720, A PROMISING NEW type of immunosuppressive agent, is a synthetic structural analog of myriocin, a metabolite of the ascomycete Isaria Sinclairii. Its chemical structure and mechanism of action are different from those of cyclosporine A (CsA), FK506, and other current immunosuppressants. FTY720 modifies lymphocyte trafficking through alteration of the expression or function of certain adhesion molecules. FTY 720 provokes migration of lymphocytes from the peripheral blood to the secondary lymphoid tissues and, as a consequence, a peripheral lymphocytopenia is observed. We already reported that FTY720 has marked anti-acute rejection properties. We also showed that FTY720 does not block tolerance in a model where an heart alloTx is spontaneously accepted after donor specific blood transfusion. Chronic allograft vasculopathy (CAV) remains a leading cause of graft failure after organ Tx. There are no data available on the effect of FTY720 on CAV. Here we investigated the effect of combined use of FTY720 and CsA on CAV in a rat heart transplantation model.

PROPE TOLERANCE: A MORE REALISTIC APPROACH TO IMPROVE LONG-TERM OUTCOMES FOR PEDIATRIC LIVING-DONOR LIVER TRANSPLANTATION: 2284

H. Ohe1, T. Koshiba2, Y. Li2, S. Sakaguchi2, K.J. Wood3, S.R. Calne4, S. Uemoto2 1Department Of Surgery, Kyoto University Grasuate School of Medicine, Kyoto/JAPAN, 2Hepatopancreatobillary Surgery And Liver Transplantation, Kyoto University Hospital, Kyoto/JAPAN, 3Transplantation Research Immunology Group, Nuffield Department of Surgery, University of Oxford, Oxford/UNITED KINGDOM, 4Surgery, University of Cambridge, CB2 2AS/UNITED KINGDOM

ADOPTIVE TRANSFER OF EX VIVO DONOR ALLOANTIGEN-STIMULATED REGULATORY T CELLS COMBINED WITH LOW DOSE TACROLIMUS AMELIORATES REJECTION OF LUNG TRANSPLANTATION BETWEEN FULLY MISMATCHED MINIATURE SWINES: 3161

(Background) An adoptive cell transfer of regulatory T cells (Tregs) has been successful in rodent Tx models,but little is known about its potential in large animal Tx models. (Method) Fully mismatched miniature swines (two haplotypes; C1 and C2), weighing 20-30kg, were used as recipients and donors. Orthotopic lung Tx was performed. The peripheral blood mononuclear cells were obtained from recipients by apheresis and CD4+CD25++ cells were isolated by magnet beads system on pre-Tx day 2. They were stimulated by donors APC with IL-2 and rapamycin until postoperative day (POD) 10 when cultured CD4+CD25++ cells (106 cells/ kg) were transferred into recipients in the presence of leukopenia induced by cyclophosphamide. High-dose tacrolimus was used from Tx to POD 6, which was followed by low-dose tacrolimus from POD 7 to 21(Group-Tregs+TAC,n=5). Graft survivals were compared with those in other groups where low dose tacrolimus alone (POD7 to 21) (Group-TAC,n=4), Tregs transfer alone (POD10) (Group-Tregs,n=3), and neither low dose tacrolimus nor Tregs transfer(Group-non TAC,non Tregs, n=2) was given. High-dose tacrolimus was given to all the groups(Tx to POD6). Open biopsy of grafts was performed at the time of transfer and 4 days after transfer and FOXP3mRNA level was semiquantified by RT-PCR. (Results) In Group-non TAC,non Tregs, graft was rejected on POD15.5. Adjunction of low dose tacrolimus alone or Tregs transfer alone did not prolonged survivals (Group-TAC and-Tregs; POD16.3 and 15). However, in the presence of Tregs transfer and low dose tacrolimus, survival was the greatest (Group-Tregs+TAC ; POD 51.0, p<0.01 vs Group-TAC, -Tregs and -non TAC, non Tregs). In this group, one recipient was rendered tolerance (>POD100). An increase of intra-graft FOXP3 expression was observed in 4 days after Tregs transfer only in Group-Tregs+TAC, but not in other groups. (Conclusions) Adoptive transfer of ex vivo donor alloantigenstimulated Tregs combined with low dose tacrolimus ameliorates rejection of immunogenic lung Tx in clinically relevant miniature swines. Early accumulation of Tregs was observed in tolerized grafts but not rejecting grafts.

Intestinal transplantation: from the laboratory to the clinics.

Abstract The intestine has long been seen as a “forbidden” organ to transplant. This is because the first attempts at Intestinal Transplantation (ITx) were defeated by rejection, technical problems, infection and graft versus host disease. Results of ITx have improved in the short-term (70 to 80% 1-year patient survival) but remain inferior to other solid organ transplants in the long-term (5 years patient survival of 50% or less). Reasons for this difference between intestine and other organ transplants are reviewed. Development of immunomodulatory protocols - e.g. protocols aiming at reducing the rejection response and facilitating engraftment - are described. Our center experience with a consecutive series of five intestinal transplants utilizing a new protolerogenic protocol and low immunosuppression is described. At time of writing, these five patients are rejection-free, nutritionally independent and lead a normal life.