Critical Role for IL-4 in the Development of Transplant Arteriosclerosis in the Absence of CD40-CD154 Costimulation

Abstract

Blockade of the CD40-CD154 pathway can inhibit CD4+ T cell activation but is unable to prevent immune responses mediated by CD8+ T cells. However, even in the absence of CD8+ T cells, inhibition of the CD40-CD154 pathway is insufficient to prevent the development of transplant arteriosclerosis. This study investigated the mechanisms of transplant arteriosclerosis in the absence of the CD40 pathway. C57BL/6 CD40−/− (H2b) recipients were transplanted with MHC-mismatched BALB/c (H2d) aortas. Transplant arteriosclerosis was evident in both CD40−/− and CD40+/− mice (intimal proliferation was 59 ± 5% for CD40−/− mice vs 58 ± 4% for CD40+/− mice) in the presence or absence of CD8+ T cells (intimal proliferation was 46 ± 7% for CD40−/− anti-CD8-treated mice vs 50 ± 10% for CD40+/− anti-CD8-treated mice), confirming that CD8+ T cells are not essential effector cells for the development of this disease. In CD40−/− recipients depleted of CD8+ T cells, the number of eosinophils infiltrating the graft was markedly increased (109 ± 24 eosinophils/grid for CD40−/− anti-CD8-treated mice vs 28 ± 7 for CD40+/− anti-CD8-treated mice). The increased presence of eosinophils correlated with augmented intragraft production of IL-4. To test the hypothesis that IL-4 was responsible for the intimal proliferation, CD8 T cell-depleted CD40−/− recipients were treated with anti-IL-4 mAb. This resulted in significantly reduced eosinophil infiltration into the graft (12 ± 5 eosinophils/grid for CD40−/− anti-CD8+, anti-IL-4-treated mice vs 109 ± 24 for CD40−/− anti-CD8-treated mice), intragraft eotaxin, CCR3 mRNA production, and the level of intimal proliferation (18 ± 5% for CD40−/− anti-CD8+-, anti-IL-4-treated mice vs 46 ± 7% for CD40−/− anti-CD8-treated mice). In conclusion, elevated intragraft IL-4 production results in an eosinophil infiltrate and is an important mechanism for CD8+ T cell-independent transplant arteriosclerosis in the absence of CD40-CD154 costimulation.

Prolonged Blockade of CD40-CD40 Ligand Interactions by Gene Transfer of CD40Ig Results in Long-Term Heart Allograft Survival and Donor-Specific Hyporesponsiveness, But Does Not Prevent Chronic Rejection

“…IgG alloantibody responses were profoundly inhibited in rats expressing CD40Ig, a finding common to some (24,25,36,38,39), but not all (19) transplantation models by blocking or in the absence of CD40-CD40L interactions. Ab responses against T cell-dependent cognate Ags were partially conserved at early time points and completely normal in recipients with long-surviving grafts, and this may be explained by the higher serum concentration of CD40Ig at early compared with late time points.…”

“…Among them, CD8 ϩ cells and eosinophils have been shown to be responsible for chronic rejection in models of CD40-CD40L blockade (23,25). Immunohistology of long-surviving hearts showed the presence of moderate perivascular infiltration by CD8␣ ϩ cells and a lower proportion of CD8␤ ϩ cells (Fig.…”

“…Several leukocyte types have been implicated in the development of chronic rejection (2,25,(33)(34)(35). Among them, CD8 ϩ cells and eosinophils have been shown to be responsible for chronic rejection in models of CD40-CD40L blockade (23,25).…”

“…In recipients with long-surviving grafts, evidence for true donor-specific tolerance (as defined by permanent graft survival with acceptance of second donor, but not third party-derived grafts in the absence of immunosuppression and of chronic rejection (21,22)) has not been formally proven. Furthermore, the absence of CD40-CD40L interactions did not prevent the development of chronic rejection in mice, but the mechanisms implicated have not been clearly established (18,(23)(24)(25).…”

Interaction Between ICOS-B7RP1 and B7-CD28 Costimulatory Pathways in Alloimmune Responses In Vivo

“…In part this is because of the failure of costimulatory blockade (targeting B7 and CD40 pathways) to completely abrogate alloreactive T-cell activation, especially in stringent transplant models (4)(5)(6)30). Recently, it has been appreciated that a number of alternative costimulatory pathways, such as the ICOS-B7RP1 pathway, exist and that these may serve to fully activate the alloreactive T cells (7,(31)(32)(33).…”