An Antibody Combination That Targets Activated T Cells Extends Graft Survival in Sensitized Recipients

Abstract

†The authors contributed equally to this work.Memory T cells are the very essence of adaptive immunity with their rapid and efficient response to antigen rechallenge and long-term persistence. However, it is becoming increasingly evident that when primed with self or transplanted tissue, these cells play a key role in causing and perpetuating tissue damage. Furthermore, current treatments, which efficiently control the naive response, have limited effects on primed T cells. We have used a treatment based on a combination of antibodies specific for molecules expressed by activated T lymphocytes to selectively remove these cells. This approach, which we termed multi-hit therapy, leads to cumulative binding of antibodies to the target T cells and a striking prolongation of skin graft survival in presensitized recipients in a stringent skin transplant model. The findings are consistent with the depletion of graft-specific CD4+ and CD8+ T cells, although other modes of action, such as T-cell regulation and altered migration could play a role. In conclusion, our therapeutic strategy controls primed T cells which are a major driving force in the pathology of many autoimmune diseases and in transplant rejection.

Antibody combination therapy targeting CD25, CD70 and CD8 reduces islet inflammation and improves glycaemia in diabetic mice

“…However, at present it remains unclear whether the depletion of T effector cells is responsible for the efficacy of antibody therapy in the NOD model. The synergy between CD70-and CD8-specific antibodies in targeting activated T cells has been described previously [6]. However, the role of CD25-specific antibody within a combination therapy is less clear.…”

“…Our published work provides evidence that when used as individual reagents antibodies specific for CD25, CD70 and CD8 are not effective in controlling primed/memory T cells [6,31]. As primed T cells play a key role in the later stages of islet pathology in NOD mice with established diabetes [32][33][34], these antibodies are highly unlikely to show effects when used as individual reagents.…”

“…Indeed, this success has now been replicated in the autoimmune diabetes setting, implying that the mechanisms of action of the therapy may be similar in these two settings. The transplant model offers some advantages in mechanistic studies, therefore most of the insights into the effects of this specific antibody combination therapy are from this model [6,11,30,35].…”

“…CD25 and CD70 are expressed on activated T cells and ensure selective targeting of effector T cells, which could be involved in islet destruction. In this strategy, a low dose of CD8-specific antibody is added to the combination therapy to increase total antibody binding to CD8 + T cells as the activated, primed CD8 + T cells are less sensitive to treatment with CD25-and CD70-specific antibodies [6]. We have focused on activated T cells as the probable effector cells critical for the islet destruction.…”

“…We have focused on the use of a combination of antibodies, as opposed to a single antibody, although most of the currently developed therapeutics in both research and the clinic are based on the use of the single compound. Our reasoning is that by increasing the quantity of antibody bound to selected target T cells a threshold should be reached that will result in their efficient control or depletion [6,11], as well as the increasing acceptance that a complex disease such as T1D will most probably require a combination approach [12].…”