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

Abstract

Previous work on blockade of CD40-CD40 ligand interaction in mice and primates with anti-CD40 ligand mAbs has resulted in a moderate prolongation of allograft survival without the development of true allograft tolerance. In this study, we show in rats that adenovirus-mediated gene transfer of CD40Ig sequences into the graft resulted in prolonged (>200 days) expression of CD40Ig and in long-term (>300 days) survival. Recipients expressing CD40Ig displayed strongly (>90%) inhibited mixed leukocyte reactions and alloantibody production at early (days 5 and 17) and late time points (>100 day) after transplantation, but showed limited inhibition of leukocyte infiltration and cytokine production as evaluated by immunohistology at early time points (day 5). Recipients of long-surviving hearts showed donor-specific hyporesponsiveness since acceptance of second cardiac allografts was donor specific. Nevertheless, long-term allografts (>100 days) displayed signs of chronic rejection vasculopathy. Occluded vessels showed leukocyte infiltration, mainly composed of CD4+ and CD8+ cells, macrophages, and mast cells. These recipients also showed antidonor CTL activity. Recipients expressing CD40Ig did not show nonspecific immunosuppression, as they were able to mount anticognate immune responses that were partially inhibited at early time points and were normal thereafter. We conclude that gene transfer-mediated expression of CD40Ig resulted in a highly efficient inhibition of acute heart allograft rejection in rats. This treatment induced donor-specific inhibition of certain alloreactive mechanisms in the short-, but not the long-term, which resulted in long-term survival of allografts concomitant with the development of chronic rejection.

Leukocyte-Targeted Myocardial Contrast Echocardiography Can Assess the Degree of Acute Allograft Rejection in a Rat Cardiac Transplantation Model

“…Although T cells play a central role in graft rejection, 12 infiltration of T cells is accompanied by monocyte/macrophage infiltration [11][12][13][14][15] because of their close interactions. 10,15 Agents that affect primarily T cells, 12 including CsA, 16,17 can also limit monocyte/macrophage infiltration.…”

“…10,15 Agents that affect primarily T cells, 12 including CsA, 16,17 can also limit monocyte/macrophage infiltration. 10,16 Indeed, the extent of macrophage infiltration as assessed by MRI with a magnetic contrast agent targeted to those cells was shown to allow detection of acute cardiac rejection in rats.…”

Gene Therapy Progress and Prospects: Gene therapy in organ transplantation

“…Expression of CD40-Ig in rat cardiac transplants has also been shown to delay acute rejection, although, at early time points after transplantation, recipients of gene-modified hearts exhibited nonspecific immunosuppression. 10 At later time points, nonspecific immunosuppression abated and responses to third-party alloantigens were restored. However, when immune responses to third-party antigens were restored, antidonor T-cell activity returned in these animals, and was associated with chronic rejection.…”

“…However, when immune responses to third-party antigens were restored, antidonor T-cell activity returned in these animals, and was associated with chronic rejection. 10 The development of chronic rejection suggests that intragraft expression of CD40-Ig needs to be complemented by other therapeutic strategies to obtain long-term transplant survival.…”

Tolerance induction by costimulator blockade in 100 cGy treated hosts with varying degrees of genetic disparity

“…Other groups also have shown the effectiveness of CD40-CD40L interaction blockade in the induction of tolerance for both hematopoietic 16,17 and nonhematopoietic tissues. [18][19][20][21] We have previously evaluated transplant models of H2-mismatched marrow using the following approach 22 ( Figure 1):…”