Altered Distribution of H60 Minor H Antigen-Specific CD8 T Cells and Attenuated Chronic Vasculopathy in Minor Histocompatibility Antigen Mismatched Heart Transplantation in Cxcr3−/− Mouse Recipients

Abstract

Chemokine-chemokine receptor interactions and the subsequent recruitment of T lymphocytes to the graft are believed to be among the initial events in the development of acute and chronic rejection of heart transplants. We sought to determine the role of chemokine receptor Cxcr3 on the development of acute and chronic rejection in a multiple minor Ag mismatched mouse heart transplant model. The frequencies and kinetics of immunodominant H60 (LTFNYRNL) miHA-specific CD8 T cells in wild-type or Cxcr3−/− C57BL/6 recipients were monitored using MHC class I tetramer after BALB/b donor hearts were transplanted. Acceptance of grafts, severity of rejection, and infiltration of T cells were not altered in Cxcr3−/− recipients. However, graft survival was moderately prolonged in Cxcr3−/− recipient mice undergoing acute rejection. Analyses of splenocytes, PBLs, and graft-infiltrating cells revealed increased alloreactive T cells (H60-specific CD8 T cells) in the peripheral blood and spleen but not in the graft. Adoptively transferred Cxcr3−/− CD8 T cells in the BALB/b heart-bearing B6 scid mice showed retention of alloreactive CD8 T cells in the blood but less infiltration into the graft. Cxcr3−/− recipients with long-term graft survival also showed a marked decrease of CD8+ T cell infiltration and reduced neo-intimal hyperplasia. These data indicate that Cxcr3 plays a critical role in the trafficking as well as activation of alloreactive T cells. This role is most eminent in a transplant model when a less complex inflammatory milieu is involved such as a well-matched graft and chronic rejection.

Overcoming Chronic Rejection—Can it B?

“…IFN-␥ elicited chemokines, such as IP-10 and MIG, may also contribute to inflammation by recruiting IFN-␥ producing T cells. We showed that reduced infiltration of CD8 T cells in a CR model using CXCR3 Ϫ/Ϫ mice alleviated CR (26). In accordance with this, induction of IFN-␥ inducible chemokine transcripts (such as MIG, IP-10, I-TAC, and RANTES) in endomyocardial biopsies showed an association with the development of graft arteriosclerosis (27)(28)(29).…”

“…In accordance with this, several groups showed a beneficial effect of targeting these chemokine receptors on CR (86 -90). We also showed that Cxcr3Ϫ/Ϫ knockout mouse recipients of cardiac allografts showed reduced neointimal hyperplasia with less CD8 T-cell infiltration (26). Combined blockade of Cxcr3/Ccr5 showed a beneficial effect on chronic allograft vasculopathy in the setting of a full MHC full mismatch (91).…”

“…The MHC II mismatched model (Bm12-B6) with cardiac allografts has been used commonly (24). Transplanting heterotopic cardiac grafts across minor histocompatibility barriers using inbred strains of mice (26,51) or a fully mismatched combination with treatments such as costimulation blockade, and gallium nitrate (52, 53) allows a reproducible CR model (Fig. 1).…”

Chemokines and Transplant Vasculopathy

“…However, several recent reports have not been able to reproduce similar beneficial effects. Two independent groups have reported that CXCR3 −/− and control mice reject full MHC mismatched donor hearts at the same rate 115, 116. These studies also showed that T-cell infiltration into the rejected hearts were similar in the 2 groups.…”

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.…”