Mice with severe insulin-dependent diabetes have woncomplete and durable remissions following a short course ofmonoclonal antibody treatment. "If confirmed in humans, ourresults will open a new era in the immunotherapy ofautoimmune diabetes," said immunologist Lucienne Chatenoudof France's National Institute for Health and Medical Research(INSERM).
Chatenoud heads a team at INSERM, where she told BioWorld"there is a very big interest for autoimmunity in general anddiabetes in particular." Last week's Proceedings of the NationalAcademy of Sciences (PNAS) reported her success in a papertitled "Anti-CD3 antibody induces long-term remission of overtautoimmunity in non-obese diabetic mice."
Non-obese diabetic mice (better known as "NOD" mice toresearchers) develop spontaneous, full-blown diabetes at 15 to25 weeks PP when they are teen-agers by human standards.This genetic propensity makes them useful models for studyingthe disease. Researchers can hasten the onset of murinediabetes through injections of cyclophosphamide, a cancerchemotherapy drug that also selectively destroys the Tlymphocytes of the immune system that holds the autoimmuneeffect in check.
That mayhem parallels the devastation wreaked on b cells by Tlymphocytes that run amok in human autoimmune diabetes.This is the process that the INSERM group reversed byunleashing its anti-CD3 monoclonal antibodies PP potentimmunosuppressive agents PP against the out-of-control T cells.
Chatenoud's group started by sending a hybridoma, donated bythe University of Chicago's Jeffrey Bluestone, to Celltech Ltd. inEngland. That company, she said, "which normally producesantibodies for human therapy, produced the anti-CD3 antibodyfor us in great amount and purity."
She administered five daily injections of the anti-CD3 antibodyfirst in NOD mice given cyclophosphamide (CY) to trigger thediabetic process, then in animals gradually acquiring thespontaneous disease. This monoclonal targeted precisely thosespecific T cell/CD3 complexes that were mounting the anti-bcell autoimmune onslaught.
In the CY-induced NOD models, PNAS reported, the antibody"was highly effective both in preventing progression to insulin-dependent diabetes mellitus and in reversing overt disease."
In two separate random, placebo-controlled experiments withsome 60 or 70 mice of the spontaneous NOD group, the PNASpaper reported, diabetes regressed in 64 percent and 80percent, respectively. This effect lasted until the animals werekilled at four months. Very recent repeat trials, Chatenoud toldBioWorld, showed that "the remission has been prolonged overseven to eight months, with no relapses yet."
Reversing autoimmunity is one thing, but preserving normalimmunity is another. Did the experimental anti-CD3 treatmentleave the NOD mice with severe immunodeficiency? To testthis, the INSERM group performed foreign-skin transplants.These were normally rejected by mice in anti-CD3-inducedremission, which showed that the animals were notimmunocompromised.
"To show the specificity of the effect, you need to show thatthere is something specifically directed to the b cell,"Chatenoud explained. "So we transplanted syngeneic islet graftscontaining b cells into the 40 percent minority of our treatedmice that had failed remission, and into untreated, overtlydiabetic controls.
"The latter promptly rejected the grafted cells, by a relapse ofthe autoimmune attack," Chatenoud said. "But the animals thathad been treated with anti-CD3 did not relapse because theanti-anti-immune treatment restored immune tolerance to the'self' antigen; that is, it reversed the autoimmunity.
"Indeed," Chatenoud continued, "syngeneic islets led to fullmetabolic reconstitution of NOD mice that were still diabeticfour to five weeks after anti-CD3 treatment." Those mice putthe new b cells to work producing insulin.
Although aiming "some day to push this type of strategy intothe clinic," Chatenoud and her group are still pursuing fullerunderstanding of the molecular mechanisms that must comefirst. They are now characterizing a second-generation anti-CD3antibody lacking the severe side effects, however transient andreversible, that characterize the only monoclonal antibodyapproved to date for use in humans (namely OKT3) given inorgan transplantation to prevent and treat allograft rejection.
Meanwhile, she suggested that her group's results so far "willencourage pharmaceutical companies to take over productionof these second-generation antibodies in a fast way." Some suchcompanies, she said, have already expressed interest.
It may be possible to apply this approach to other autoimmunediseases, Chatenoud said, but "it's less easy in diseases that,unlike diabetes, are not organ-specific." All in all, she added,"it's for sure a new and fascinating way of envisioning humanimmunotherapy."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.