The use of a non‐depleting anti‐CD4 monoclonal antibody to re‐establish tolerance to β cells in NOD mice

Abstract

The use of immunosuppressive drugs in the management of autoimmunity penalizes a large part of the immune system for the misdemeanors of a small minority of T cells. An ideal form of therapy would be one in which it were possible to render the immune system tolerant of the inciting antigens with minimal effects on other responses. We here show that it is possible to re-establish self tolerance in an animal model of insulin-dependent diabetes mellitus without prior deletion of CD4+ T cells using a short course of therapy with a non-lytic monoclonal antibody to the CD4 adhesion receptor on T cells. This tolerance can be achieved even when diabetogenic cells are already in the pancreas. Primary responses to antigens given after therapy has ceased are normal and secondary responses to antigens seen prior to, but not during, the period of antibody therapy can remain unaffected. This suggests that intervention with selected CD4 antibodies may have significant advantages over and above that provided not only by conventional immunosuppression but also over that provided by a depleting antibody.

Production of erythrocyte autoantibodies in NZB mice is inhibited by CD4 antibodies

“…These findings are consistent with several other studies in which anti-CD4 antibodies were successfully used either to retard, prevent or reverse the clinical and immunological manifestations of several murine models of autoimmune diseases such as diabetes in NOD mice [14,20,21], collagen-induced arthritis in DBA/1 mice [15], systemic lupus erythematosus (SLE) in NZB/NZW F, [11,12] and BXSB mice [13], and chronic relapsing encephalomyelitis in SJL/J [16], In these long-term experiments we have used saline rather than an irrelevant rat MoAb since the experiments of Wofsy [23] with BXSB mice showed that mice receiving rat IgG over a long period died prematurely, presumably due to T-dependent anti-rat antibodies. This cannot occur when the T cells are compromised by the anti-CD4 specificity ofthe rat antibodies [13,18], In NZB mice, the autoimmune response has previously been .shown to be T cell-dependent in vitro [10].…”

Anti-coreceptor therapy drives selective T cell egress by suppressing inflammation-dependent chemotactic cues

“…Administration of YTS105 blocks progression of insulitis and clinical onset in prediabetic NOD mice either in the context of spontaneous disease or in a T cell transfer model (43,44). Similarly, YTS177 is effective at preventing T1D and resolving insulitis in NOD mice after transfer of either diabetogenic splenocytes or primed BDC CD4 + T cells (35,45). The latter is associated with downregulation of IL2 and IFNG gene expression.…”

Nondepleting Anti-CD4 Has an Immediate Action on Diabetogenic Effector Cells, Halting Their Destruction of Pancreatic β Cells

“…However, one of the striking features of such mAb-mediated tolerance is the arrest of the process whereby primed effector T cells destroy target tissues. In the NOD mouse model of IDDM, nondepleting anti-CD4 Abs have been shown to be effective in preventing IDDM even at a stage when primed T cells were already in the pancreatic islets (11). This raised the possibility that there may be a direct effect of such Ab treatment on the effector T cells and that its efficacy was not wholly attributable to inhibition of T cell priming and induction of regulatory T cells.…”

“…Our previous studies have shown that the monoclonal nondepleting rat IgG2a anti-CD4, YTS 177, can prevent spleen cells from diabetic NOD mice from transferring IDDM to irradiated NOD recipients (11). We and others have been able to demonstrate that one of the ways in which this Ab may generate and maintain peripheral tolerance is through the generation of regulatory T cells (15, 21; and reviewed in Ref.…”

“…Previous work from our group has shown that the nondepleting anti-CD4 Ab YTS 177 can stop the transfer of diabetes with diabetic spleen cells at a late stage in the disease process when primed T cells are in the islet and there has been marked recruitment of inflammatory cells (11). Therefore, it is worth considering the mechanism(s) by which mAbs specific for T cells exert their tolerogenic function, as they appear to offer the most efficacious approach.…”