OX40 Costimulation Prevents Allograft Acceptance Induced by CD40-CD40L Blockade

Abstract

Disrupting the CD40-CD40L costimulation pathway promotes allograft acceptance in many settings. Herein, we demonstrate that stimulating OX40 overrides cardiac allograft acceptance induced by disrupting CD40-CD40L interactions. This effect of OX40 stimulation was dependent on CD4+ T cells, which in turn provided help for CD8+ T cells and B cells. Allograft rejection was associated with donor-reactive Th1 and Th2 responses and an unconventional granulocytic infiltrate and thrombosis of the arteries. Interestingly, OX40 stimulation induced a donor-reactive IgG class switch in the absence of CD40-CD40L interactions, and the timing of OX40 stimulation relative to transplantation affected the isotype of donor-reactive Ab produced. Inductive OX40 stimulation induced acute graft rejection, which correlated with both IgG1 and IgG2a deposition within the graft. Once graft acceptance was established following CD40-CD40L blockade, delayed OX40 stimulation did not induce acute allograft rejection despite priming of graft-reactive Th1 and Th2. Rather, chronic rejection was induced, which was characterized by IgG1 but not IgG2a deposition within the graft. These studies reveal both redundancy and key differences in function among costimulatory molecules that manifest in distinct pathologies of allograft rejection. These findings may help guide development of therapeutics aimed at promoting graft acceptance in transplant recipients.

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

“…[7][8][9] This, in turn, upregulates APC costimulatory molecule (CD80/86) and major histocompatibility complex expression and induces pro-inflammatory cytokines (eg, IL-12), 10 which promote CD8 ϩ T-cell activation, expansion, differentiation, and survival. 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.…”

CD40-Independent Help by Memory CD4 T Cells Induces Pathogenic Alloantibody But Does Not Lead to Long-Lasting Humoral Immunity

“…For example, CD134 expressed by T helper cells and CD134L expressed on activated B cells are involved in T/B cell interactions during productive humoral immune responses (19, 20). Furthermore, CD134 stimulation with agonistic anti-CD134 mAb induced production of anti-donor IgG alloantibody in CD40−/− heart allograft recipients (21). Future studies will determine whether CD134/CD134L pathway compensates for the lack of CD40 and drives B cell differentiation and alloantibody production in our system.…”

Transient Blockade of Delta-like Notch Ligands Prevents Allograft Rejection Mediated by Cellular and Humoral Mechanisms in a Mouse Model of Heart Transplantation

“…As described (38, 41), P815 (H-2 d ) cells (American Type Culture Collection, Manassas, VA) were stained for flow cytometric analysis using a 1/50 dilution of sera obtained from cardiac allograft recipients as the primary antibody, followed by FITC-conjugated rabbit anti-mouse IgG antibody (Invitrogen Life Technologies, Grand Island, NY) used at a 1/50 dilution. Data are reported as the mean channel fluorescence determined on a Becton Dickinson FACScan (San Jose, CA).…”