CD40 Signaling Replaces CD4+ Lymphocytes and Its Blocking Prevents Chronic Rejection of Heart Transplants

Abstract

Chronic rejection remains the major obstacle to long term survival in heart transplant recipients. The cellular and molecular mechanisms that underlie chronic rejection are not known, and their discovery can form the basis of clinical intervention. Several investigators have suggested that the development of chronic rejection in solid organ transplants is dependent on help mediated by CD4+ lymphocytes. Importantly, the mechanism through which help is provided has not been fully delineated in transplant rejection. Using a murine heterotopic heart transplant model without immunosuppression, this study defines the functional role of CD4+ lymphocytes in chronic rejection. In an MHC class II-mismatched model, we demonstrate that chronic rejection was absolutely contingent on the presence of CD4+ lymphocytes. Importantly, here we report that signaling through CD40 can replace the requirement of CD4+ lymphocytes, demonstrated by the development of chronic rejection in CD4 knockout recipients treated with a CD40-activating mAb (FGK45). The return of rejection appears to be a CD8+ lymphocyte-dependent process, noted by the absence of rejection in FGK45-treated recombinase-activated gene knockout (CD4+ and CD8+ lymphocyte-deficient) recipients. The CD40 signaling pathway works independently of B7-CD28 costimulation, as indicated by the development of severe chronic rejection in CD28 knockout recipients. Importantly, this study provides evidence that CD40 ligand-targeted therapies may prevent chronic rejection only in strain combinations where CD4+ lymphocyte help is absolutely required.

PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice

“…Agonistic anti-CD3 and anti-CD28 Abs were obtained from eBioscience. The FGK45 agonistic anti-CD40 Ab has been previously described (62). OVA257-264 peptide (SIINFEKL; OVAp) and its low-affinity variant E1 (EIINFEKL) were purchased from Anaspec.…”

Complement Regulates CD4 T-Cell Help to CD8 T Cells Required for Murine Allograft Rejection

“…These concepts are supported by findings in murine transplant experiments that survival of allogeneic heart grafts in CD40 Ϫ/Ϫ recipients is markedly prolonged 11,12 and that cross-linking CD40 in CD4-deficient mice reconstitutes CD8-mediated allograft injury. 13 Previous work by our joint group indicates that CD4 ϩ T-cell/DC interactions induce local production of C3a and C5a which bind to C3a/C5a receptors (C3aR, C5aR) on T cells, stimulating T-cell proliferation and survival. 14 -16 These published findings suggest that one molecular mechanism through which CD4 ϩ T cells might provide help in inducing an alloreactive CD8 ϩ T-cell response to a transplant is through stimulating local C3a/C5a production by the APC, which then could activate the CD8 cells by ligating C5aR/C3aR on their surfaces.…”

Combined Blockade of the Chemokine Receptors CCR1 and CCR5 Attenuates Chronic Rejection

“…Because CAV in this model is a T lymphocyte-dependent process, 20 inhibition of T lymphocyte recruitment alone may be the most important mechanism by which Met-RANTES reduces CAV. However, macrophages are also believed to play a pathogenic role in human CAV.…”