Impact of donor MHC class I or class II antigen deficiency on first‐ and second‐set rejection of mouse heart or liver allografts

Abstract

SUMMARYThe influence of donor major histocompatibility complex (MHC) class I-or class II-deficiency on the initiation of first-and second-set rejection of mouse heart and liver allografts was examined. C3H (H-2 k ) mice received heterotopic cardiac or orthotopic liver grafts from unmodified B10 (H-2 b ), B6 (H-2 b ), b2m (H-2 b ; class I deficient) or AB 0 (H-2 b ; class II deficient) donors. Organ survival was also investigated in C3H recipients that had been presensitized by a normal B10 skin graft 2-3 weeks before heart or liver transplantation. The absence of cell surface MHC class I or class II resulted in significant prolongation of primary cardiac allograft survival. Three of seven (43%) MHC class I-deficient, and two of five (40%) class II-deficient heart grafts were accepted indefinitely (survival time >100 days). Thus both MHC class I and class II molecules appear to be important for the elicitation of first-set rejection in the heart allograft model. All liver allografts survived >100 days in normal recipients. In C3H recipients that had been presensitized by a B10 skin graft, however, both heart and liver grafts from AB 0 (class II deficient) donors underwent accelerated rejection (median survival time [MST] 3 and 4 days, respectively). In contrast, liver grafts from class I-deficient mice (b2m) were still accepted indefinitely by B10 skin-presensitized C3H recipients, whereas class I-deficient hearts survived significantly longer than those from class II-deficient or normal donors. These data demonstrate that the expression of donor MHC class I, and not class II is crucial in initiating second-set organ allograft rejection. In vitro monitoring revealed that at the time of organ transplant, both splenocytes and serum of the skinpresensitized animals displayed high cytotoxicity against AB 0 (class II-deficient) but not against b2m (class I-deficient) targets.

Immune activation is required for the induction of liver allograft tolerance: Implications for immunosuppressive therapy

“…29 However, it is not believed to be the principal means of liver allograft tolerance because some experiments showed it was ineffective in prolonging graft survival, 26 and tolerance still occurred when MHC class I-deficient livers were transplanted. 30 More recently, it has been proposed that the liver may also inhibit rejection through the particular characteristics of its unique vascular architecture and the immunomodulatory activity of hepatocytes. The liver is the only organ in which recirculating naive T cells directly contact parenchymal cells.…”

Analysis of the Innate and Adaptive Phases of Allograft Rejection by Cluster Analysis of Transcriptional Profiles

“…The common observation in these studies of gene-deficient mice that rejection is delayed, but not indefinitely prevented, supports a model in which multiple different components of the alloimmune response are important, but not always necessary, to induce graft rejection. Only in a few gene-deficient models, such as elimination of all T cells or both B7-1 and B7-2 costimulatory molecules, and probably the deletion of both MHC class I and II, is the graft permanently accepted without rejection (7)(8)(9)(10)(11)(12).…”

Mechanisms of T Cell Death in the Liver: To Bim or Not to Bim?

“…However, this does not exclude the potential for the liver to remove activated T cells, as suggested by the extension of tolerance from hepatic allografts to other solid organs that would normally be rejected [15,16] . In this setting, the liver is capable of tolerising recently activated allo-specific T cells, but this does not occur at later time-points [17] or when large numbers of activated T cells are present [18] , suggesting the liver has a limited capacity to induce tolerance or is unable to tolerise memory T cells.…”