B.N. Nguyen

Inducing CTLA-4–Dependent Immune Regulation by Selective CD28 Blockade Promotes Regulatory T Cells in Organ Transplantation

An improved method of immunosuppression allows better immune function and prolongs the survival of transplanted organs in nonhuman primates. Increasing Tolerance with Less Toxicity According to Chinese legend, 2500 years ago the physician Pien Ch’iao exchanged the hearts of two warriors, one of strong spirit and weak will and the other of weak spirit and strong will, with the aim of achieving balance in their characters. Of course, without modern surgical techniques and the ability to suppress organ rejection by the recipient’s immune system, such transplants would have been impossible. It was not until the discovery of the powerful immunosuppressant drug cyclosporin that organ transplants between unrelated individuals became routinely successful, beginning in the 1980s. Cyclosporin and some newer similar drugs, however, have toxic side effects, and none of them can stop eventual rejection of the organ, so researchers are seeking other options. Now, Vanhove and colleagues test an alternative immunosuppressive strategy. T cells are a major culprit in the immune response directed against transplanted organs, and therefore a number of immunosuppressive drugs target T cells. Cyclosporin, for example, inhibits calcineurin, a protein phosphatase that under normal conditions increases the expression of interleukin 2, which—among other functions—promotes the proliferation of activated T cells. Certain newer approaches to immunosuppression target the process by which T cells become activated. In general, this process is induced by antigen binding to the T cell receptor and reinforced by costimulatory molecules—CD80 and CD86—binding to the T cell CD28 receptor. Additionally, CD80/86 can bind to the CTLA-4 receptor, resulting in T cell inhibition. CTLA-4 is also required for the function of regulatory T cells (Tregs), which suppress aberrant immune responses and are important for inducing tolerance toward transplanted tissue. Several drugs that block CD80/86 have been developed as a nontoxic alternative to calcineurin inhibitors, but in addition to affecting the CD28-mediated pathway of T cell stimulation, these reagents also inhibit the CTLA-4 signals required for Treg function. To avoid inhibiting CTLA-4–dependent regulation of the immune system while suppressing T cell activation, the Vanhove, Blancho, and Pierson labs aimed to block CD28 function directly in experiments on kidney and heart transplantation in baboons and monkeys. Previous work showed that down-regulation of CD28 activity with an anti-CD28 monoclonal antibody inhibited rejection of organ transplants in rodents. For the new nonhuman primate studies, the researchers used a fragment of a human CD28-specific monoclonal antibody fused to a carrier molecule to increase its half-life in vivo. This fusion antibody, sc28AT, recognizes CD28 from monkeys and baboons as well as humans, and it competes with CD80/86 for binding to CD28. sc28AT increased the number of functional Tregs and reduced chronic rejection of the transplanted tissue in the primates when used together with a calcineurin inhibitor. This is good news because it suggests that the dose of such inhibitors (and their toxic side effects) could be reduced in patients when given with a molecule targeting CD28. It remains to be determined whether this approach offers practical advantages over straight CD80/86 blockade when tested in the clinic. Transplantation is the treatment of choice for patients with end-stage organ failure. Its success is limited by side effects of immunosuppressive drugs, such as inhibitors of the calcineurin pathway that prevent rejection by reducing synthesis of interleukin-2 by T cells. Moreover, none of the existing drugs efficiently prevent the eventual rejection of the organ. Blocking the CD28-mediated T cell costimulation pathway is a nontoxic alternative immunosuppression strategy that is now achieved by blockade of CD80/86, the receptor for CD28 on antigen-presenting cells. However, interaction of CD80/86 with cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is required for immune regulation. Therefore, CD28 blockade, instead of CD80/86 blockade, might preserve regulatory signals mediated by CTLA-4 and preserve immune regulation. By using monovalent antibodies, we identified true CD28 antagonists that induced CTLA-4–dependent decreased T cell function compatible with regulatory T (Treg) cell suppression. In transplantation experiments in primates, blocking CD28 augmented intragraft and peripheral blood Treg cells, induced molecular signatures of immune regulation, and prevented graft rejection and vasculopathy in synergy with calcineurin inhibition. These findings suggest that targeting costimulation blockade at CD28 preserves CTLA-4–dependent immune regulation and promotes allograft survival.

Co-stimulation blockade targeting CD154 and CD28/B7 modulates the induced antibody response after a pig-to-baboon cardiac xenograft

Abstract:  Background:  The induced antibodies against Galα1,3Gal (Gal) and non‐Gal epitopes may contribute to delayed xenograft rejection (DXR). We asked whether blockade of the CD40/CD154 and CD28/B7 co‐stimulatory pathways modulates the baboon elicited antibody response to pig Gal and non‐Gal antigens.

Coagulation cascade activation triggers early failure of pig hearts expressing human complement regulatory genes

Abstract:  Background:  Hyperacute rejection (HAR) and early graft failure (EGF) have been described in a minority of pig‐to‐baboon heart transplants using organs transgenic for human complement regulatory proteins (hCRP). Here we investigate the role of coagulation cascade activation in the pathogenesis of HAR and EGF in a consecutive series where a high incidence of these outcomes was observed.