Primary Vascularization of the Graft Determines the Immunodominance of Murine Minor H Antigens during Organ Transplantation

Abstract

Grafts can be rejected even when matched for MHC because of differences in the minor histocompatibility Ags (mH-Ags). H4- and H60-derived epitopes are known as immunodominant mH-Ags in H2b-compatible BALB.B to C57BL/6 transplantation settings. Although multiple explanations have been provided to explain immunodominance of Ags, the role of vascularization of the graft is yet to be determined. In this study, we used heart (vascularized) and skin (nonvascularized) transplantations to determine the role of primary vascularization of the graft. A higher IFN-γ response toward H60 peptide occurs in heart recipients. In contrast, a higher IFN-γ response was generated against H4 peptide in skin transplant recipients. Peptide-loaded tetramer staining revealed a distinct antigenic hierarchy between heart and skin transplantation: H60-specific CD8+ T cells were the most abundant after heart transplantation, whereas H4-specific CD8+ T cells were more abundant after skin graft. Neither the tissue-specific distribution of mH-Ags nor the draining lymph node-derived dendritic cells correlated with the observed immunodominance. Interestingly, non-primarily vascularized cardiac allografts mimicked skin grafts in the observed immunodominance, and H60 immunodominance was observed in primarily vascularized skin grafts. However, T cell depletion from the BALB.B donor prior to cardiac allograft induces H4 immunodominance in vascularized cardiac allograft. Collectively, our data suggest that immediate transmigration of donor T cells via primary vascularization is responsible for the immunodominance of H60 mH-Ag in organ and tissue transplantation.

Impact of Leukocyte Function-Associated Antigen-1 Blockade on Endogenous Allospecific T Cells to Multiple Minor Histocompatibility Antigen Mismatched Cardiac Allograft

“…B6 heart transplantation. 12,19 As shown in Figure 2B, peripheral H60-specific CD8 T cells from untreated animals (POD 10) demonstrated homing (CD11a hi CD44 hi CD62L lo ) and chemokine (Cxcr3 + Ccr5 + Ccr7 − ) receptor expression of a traditionally activated Th1-related cell phenotype. Through the combination of this homing/chemokine receptor expression, these cells are immunophenotypically ready to leave the secondary lymphoid organ and get to the inflammatory site.…”

“…12 The grafts were monitored by daily palpation and graded from 4+ (strongest beat) to 0 (no beat), and rejection was confirmed by laparotomy. Animals were either untreated or treated with anti-LFA-1 mAb (KBA; rat IgG2a) 200 μg, intraperitoneally on postoperation days (PODs) 0, 1, 7, and 14.…”

Lessons and Limits of Mouse Models

“…These APCs have immediate access, through lymphatic drainage, to recipient secondary lymphoid organs where they stimulate donor-reactive T cells. Vascularization of skin allografts has also been shown to impact the early transmigration of donor T cells into the draining lymph nodes that then alter the specificity, tempo, and/or intensity of the alloreactive response by recipient T cells (Kwun et al 2011). In contrast, host leukocytes including memory CD8 þ T cells may have early access to the allograft endothelium to promote early inflammation and subsequent rejection (Schenk et al 2008(Schenk et al , 2009).…”

“…When complete MHC-disparate (e.g., both class I and class II MHC allelic differences) heart allografts are heterotopically transplanted into immunocompetent recipients, they are rejected (defined as the complete cessation of heartbeat) within 7-10 d (Corry et al 1973;Schenk et al 2008Schenk et al , 2009Kwun et al 2011). Characteristics of this rejection are similar to acute cell-mediated rejection in clinical transplantation, namely, an intense mononuclear cell infiltrate that includes macrophages and T cells, with CD8 þ T cells predominating over CD4 þ T cells.…”

Bidirectional alloreactivity

“…The immediate spreading of donor T cells to host lymphoid and nonlymphoid tissues and the reduced inflammation in the setting of a vascularized transplant may also cause a shift in host indirect response toward immunogenic, but hematopoetic-restricted minor antigens, such as HA-1 in humans or H-60 in mice, causing an immundominant response less likely to harm the graft parenchyma. 48 Alternatively, this shift in immunodominance could promote the indirect activation of Tregs directed to donor MHC class I and minor antigens.…”