anti-CD20 and anti-CD3 by Hu and Wen at Yale

Combination treatment with anti-CD20 and oral anti-CD3 prevents and reverses autoimmune diabetes

Abstract: Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease, although B cells also play an important role in T1D development. Both T cell- and B cell-directed immunotherapies have shown efficacy in the prevention and reversal of T1D. However, whether the combined strategy of targeting both T and B cells could further improve the therapeutic efficacy remains to be explored. Herein we show that the combined treatment with intravenous anti-human CD20 (hCD20) and oral anti-CD3 significantly delayed diabetes development in pre-diabetic hCD20 transgenic NOD mice. More importantly, the combined treatment reversed diabetes in more than 60% of mice newly diagnosed with diabetes. Further mechanistic studies demonstrated that the addition of oral anti-CD3 to the B cell depletion therapy synergistically enhanced the suppressive function of Treg. Interestingly, the oral anti-CD3 treatment induced a fraction of IL-10-producing CD4 T cells in the small intestine through IL-10 and IL-27-producing dendritic cells. Thus, our findings demonstrated that combining anti-CD20 and oral anti-CD3 is superior to anti-CD20 monotherapy for restoring normoglycemia in diabetic NOD mice, providing important preclinical evidence for the optimization of B cell-directed therapy for type 1 diabetes.

bone marrow and cell grow factors by Zeng at University of Florida

Quote:

a new combination therapy that reverses established Type 1 diabetes in mice. ... The two-step regimen involves bone marrow transplantation and substances that promote the growth of cells that produce insulin, the sugar-regulating hormone that is missing in people who have Type 1 diabetes.

Source: http://news.ufl.edu/2012/05/09/diabetes-reversal/
News article: http://www.bloomberg.com/news/2012-05-09/immune-cell-therapy-cures-diabetic-mice-researchers-find.html

proinsulin autoantigen, IL-10, and anti-CD3 by Mathieu at KU Leuven

Quote:

Our intervention effectively reverted diabetes in newly diagnosed diabetic NOD mice, with a success rate seldom approached in NOD mice,” the authors conclude. “The therapy allowed us to exploit lower doses of anti-CD3 (ideally to circumvent side effects and undesired reactions) in combination with other interventions to enhance therapeutic efficacy. In particular, our combination therapy using L. lactis expressing PINS and hIL10 and low-dose anti-CD3 preserved functional β cell mass, resolved severe insulitis

And here was another interesting tid-bit:

Interestingly, the team reports, there was no evidence that the L. lactis-anti-CD3 therapy actually triggered beta-cell proliferation. Rather, it seemed to enable regranulation or reactivation of beta cells that had been deactivated by diabetes-related immune inflammation. This suggests that the treatment may only work when there are enough potentially functional beta cells present to start with.

News coverage:
http://www.genengnews.com/gen-news-highlights/engineered-gut-bacteria-reverse-type-1-diabetes-in-experimental-mice/81246608/
Abstract: http://www.jci.org/articles/view/60530#sd

This mouse cure is combining three different treatments and two different delivery systems, so they have got a lot going on.

The anti-CD3 drug is given by injection, so that is standard.  However the proinsulin and the IL-10 is given by genetically modifying a bacteria, and then putting that bacteria in the mouse's gut.  This avoids the problem where the proteins in proinsulin and IL-10 are digested.  Instead they are generated by bacteria right where they are absorbed into the blood stream.

As for the treatments, it's "one of everything":

• Anti-CD3 is an immune system modulator (This drug has been tried extensively in the past, and looked good early on, but failed in phase-III human tests.)
• IL-10 lowers inflammation and lowers the action of part of the immune system called NK cells. (NK "natural killer" cells is part of the immune system, but completely different than the T cells and B cells that most anti-type-1 treatments target.  Obviously, inflammation is an approach which just became popular in the last 4-7 years, and has not panned out as yet.)
• Pro-insulin is an antigen specific attempt to train the immune system not to self attack.  (Like giving peanut proteins to people allergic to peanuts.)

GABA by Prud’homme at St. Michael’s Hospital in Toronto

News coverage: http://fftimes.com/node/243716

Quotes:

A natural chemical generated by the same cells that produce insulin in the pancreas has been found to not only prevent Type 1 diabetes in mice but reverse the condition, according to a new study.
Dr. Qinghua Wang and Dr. Gerald Prud’homme of St. Michael’s Hospital in Toronto led a team of international researchers in the study. Findings were published yesterday in the journal Proceedings of the National Academy of Sciences.

lisofylline and exendin-4 by Yang at University of Virginia

Quote:

in this study we combined lisofylline to suppress autoimmunity and exendin-4 to enhance β-cell proliferation for treating autoimmune-mediated diabetes in the non-obese diabetic (NOD) mouse model. We found that this combined therapy effectively reversed new-onset diabetes within a week of therapy, and even maintained euglycemia up to 145 days after treatment withdrawal. 

Abstract: http://www.sciencedirect.com/science/article/pii/S0006291X06007066