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

Destruction of pancreatic islets in type 1 diabetes is caused by infiltrating, primed and activated T cells. In a clinical setting this autoimmune process is already in an advanced stage before intervention therapy can be administered. Therefore, an effective intervention needs to reduce islet inflammation and preserve any remaining islet function. In this study we have investigated the role of targeting activated T cells in reversing autoimmune diabetes. A combination therapy consisting of CD25-, CD70- and CD8-specific monoclonal antibodies was administered to non-obese diabetic (NOD) mice with either new-onset diabetes or with advanced diabetes. In NOD mice with new-onset diabetes antibody combination treatment reversed hyperglycaemia and achieved long-term protection from diabetes (blood glucose <13·9 mmol/l) in >50% of mice. In contrast, in the control, untreated group blood glucose levels continued to increase and none of the mice were protected from diabetes (P < 0·0001). Starting therapy early when hyperglycaemia was relatively mild proved critical, as the mice with advanced diabetes showed less efficient control of blood glucose and shorter life span. Histological analysis (insulitis score) showed islet preservation and reduced immune infiltration in all treated groups, compared to their controls. In conclusion, antibody combination therapy that targets CD25, CD70 and CD8 results in decreased islet infiltration and improved blood glucose levels in NOD mice with established diabetes.

An antibody combination that targets activated T cells extends graft survival in sensitized recipients.

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.