The Induction of Tolerance of Renal Allografts by Adoptive Transfer in Miniature Swine

Abstract

Our previous in vitro data have demonstrated that regulatory mechanisms are involved in tolerance of class I-mismatched renal allografts in miniature swine treated with 12 days of high dose Cyclsporin A. In the present study, we attempted to induce tolerance of class I-mismatched kidneys by adoptive transfer of cells and/or kidneys from long-term tolerant animals. Fifteen SLAdd miniature swine received 1.5 Gy whole body irradiation and class I-mismatched (SLAgg) kidneys from naïve pigs with or without co-transplanted kidneys and/or adoptively transferred cells from long-term tolerant (LTT) SLAdd recipients of SLAgg grafts. Additionally, three SLAdd miniature swine received class I mismatched kidney with adoptively transferred cells from LTT SLAdd recipients. Naïve kidneys transplanted without a LTT kidney were rejected within 9 days. All recipients of naive kidneys along with cells and kidney grafts from LTT animals showed markedly prolonged survival of the naive renal grafts (day 28, >150 and >150 days). These studies suggest that (1) tolerated kidneys have potent regulatory effects, and (2) cells from LTT animals infused in conjunction with kidney grafts augment these regulatory effects. To our knowledge, these studies represent the first demonstration of successful adoptive transfer of tolerance in large animals.

Abrogation of Renal Allograft Tolerance in MGH Miniature Swine: The Role of Intra-Graft and Peripheral Factors in Long-Term Tolerance

“…Primary orthotopic kidney transplantation and retransplantation in MGH swine have been previously described (5,10). At time of retransplantation, the prior tolerated graft was surgically removed and replaced with a naïve SLA-matched renal allograft.…”

“…A senior transplant pathologist scored rejection. Immunohistochemical analysis was performed as previously described (10). Graft infiltrating cells were analyzed by staining renal biopsies for CD3, CD4, CD25 and FoxP3.…”

“…Recently we demonstrated the successful adoptive transfer of tolerance in this kidney model. Data showed that adoptive transfer of both peripheral lymphocytes from long-term tolerant animals in combination with the long-term tolerated graft led to stable tolerance in recipients without further pharmacologic immunosuppression (10). Because the tolerated graft along with peripheral lymphocytes led to successful adoptive transfer of tolerance, we hypothesized that removal of these elements from a tolerant animal should abrogate tolerance.…”

Adoptive Transfer of Renal Allograft Tolerance in a Large Animal Model.

“…However, successful transfer of this tolerance required treatment of naïve recipients with: 1) 150 cGy whole body irradiation (WBI); 2) an infusion of leukapheresed PBMCs from a syngeneic recipient already tolerant of a similarly class Imismatched kidney and primed with donor-matched DST 8 days prior to PBMC harvest; and 3) simultaneous transplantation of the long-term tolerant (LTT) kidney along with the naïve class I-mismatched kidney. These results implied that both peripheral and intra-graft regulatory cells were required for transfer of tolerance to a naïve donor-matched kidney (3). In the present study, we have attempted to determine whether all off these elements were required for adoptive transfer of tolerance to the LTT kidney or whether intra-graft regulatory cells alone would suffice in the absence of an additional naïve, donor-matched kidney transplant.…”

“…Successful adoptive transfer of transplantation tolerance has only been demonstrated previously in inbred mice, perhaps because the regulatory cells thought to be responsible for this phenomenon, only survive if adoptively transferred to syngeneic recipients (1;2). Using inbred miniature swine with >94% coefficient of inbreeding, we have recently reported adoptive transfer of tolerance to a kidney transplanted across a class I MHC mismatch (3). However, successful transfer of this tolerance required treatment of naïve recipients with: 1) 150 cGy whole body irradiation (WBI); 2) an infusion of leukapheresed PBMCs from a syngeneic recipient already tolerant of a similarly class Imismatched kidney and primed with donor-matched DST 8 days prior to PBMC harvest; and 3) simultaneous transplantation of the long-term tolerant (LTT) kidney along with the naïve class I-mismatched kidney.…”