Induction of specific unresponsiveness (tolerance) to skin allografts by intrathymic donor-specific splenocyte injection in antilymphocyte serum-treated mice

Abstract

Although chronic immunosuppression has been extremely successful in clinical organ transplantation, it is associated with severe complications such as opportunistic infections, spontaneous neoplasms, drug toxicities, metabolic complications, and the inability to control rejection. We therefore have investigated the ability of allogeneic donor lymphoid cells to produce specific tolerance following intrathymic (IT) injection into allograft recipients. Groups of B6AF1 mice received ALS on days -1 and +2 relative to C3H/He skin grafts on day 0; experimental groups received 1, 5, or 10 x 10(7) syngeneic (B6AF1) or allogeneic (C3H) spleen cells (SPCs) by IT injection on day +7. IT injection of C3H splenocytes significantly prolonged allograft survival at all cell doses tested when compared with ALS controls. The best survival was obtained following IT injection of 5 x 10(7) C3H cells (median survival time [MST] = 132 days; ALS controls = 21.5 days), with 8 of 13 skin grafts surviving longer than 100 days. IT injection of syngeneic splenocytes or third-party DBA/2 splenocytes did not prolong allograft survival beyond that observed in ALS controls. C3H spleen cells injected IT into ALS treated mice on day 0 relative to grafting of C3H skin also produced significant allograft survival (1, 5, or 10 x 10(7) SPCs = MSTs of 75, 47, and 35, respectively) but the results were inferior to those obtained by 5 x 10(7) SPCs IT on day +7. Spleen cells (1 or 5 x 10(7)) injected intraperitoneally or intravenously prolonged allograft survival beyond that seen in ALS controls but were inferior to IT injection at all doses and times studied. Bone marrow, thymocytes, or lymph node cells (5 x 10(7) cells) were substituted for SPCs for IT injection. IT injection of BM, LN or thymocytes all significantly prolonged graft survival over ALS controls. However none of these cell types was as effective as IT splenocytes. Eight B6Af1 recipients of IT splenocytes bearing C3H skin grafts for > 100 days received a second C3H skin graft as well as a simultaneous third-party B10.AKM skin graft. All rejected third-party grafts in normal first-set fashion. Three tolerated both 1st and 2nd C3H grafts without any sign of rejection; 1 rejected the 2nd C3H graft while tolerating the 1st graft; and 4 rejected the 2nd C3H graft in an attenuated fashion but also rejected the 1st graft at the same pace.(ABSTRACT TRUNCATED AT 400 WORDS)