Limitations in Immunotherapy with CD3 Antibodies: Comment on the Article by Drs. Chatenoud and Bach

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The Review of Diabetic Studies,2005,2,4,187-189.
Published:February 2006
Author(s) affiliations:

Damien Bresson and Matthias von Herrath

La Jolla Institute for Allergy and Immunology, Department of Developmental Immunology 3, 10355 Science Center Drive, San Diego, California 92121, USA.


The article by Drs. Chatenoud and Bach [1] is in many aspects sophisticated as well as surging. It summarizes the latest findings on immunotherapy of type 1 diabetes (T1D) regarding the application of CD3 antibodies by scrutinizing four prevailing concepts that could mislead the further development of such therapies. Inasmuch these concepts, i.e. antigenspecific therapies, initiation of immunotherapy before diabetes onset, combining several agents and, finally, caution regarding the generalization of results obtained from NOD mice, still remain burning issues in diabetes research, the article contributes valuably to the path of finding the optimal intervention strategy. The authors present criticism to the four concepts and take a clear stand of the promise of antigen-nonspecific immunotherapy in the establishment of long-term remission. Insofar, the article inspires to a more intensive discussion to include aspects that could be able to enrich the discussion on these critical concepts. Firstly, it is noticeable that the outcomes of several investigations do not confirm the role of anti-CD3 alone as a cure for T1D in humans [2-4]. If we act on this assumption, then either additional therapies and combinations will be needed or another holistic approach to cure the disease must be taken into consideration. Another critical issue in anti-CD3 therapy is the dose of administration. The dose that is currently being used in clinical trials is probably close to the maximum that can be ethically given. This is because of the initial cytokine release syndrome and the transient EBV reactivation that occurs in many patients due to the systemically immunosuppressive properties of anti- CD3 [5-8]. In order to avoid high doses, more frequent administrations of anti-CD3 or administration during the prediabetic phase could be beneficial, although we do not know whether this strategy will be safe. In this regard, we may consider why the NOD animal model could be misleading. Although anti-CD3 did not completely protect from diabetes when given to prediabetic NOD mice, it did in other diabetes models, such as the streptozotocin-treated CD1 mice [9] and the rat insulin promoter-lymphocytic choriomeningitis virus (RIPLCMV) model [10]. Therefore, maybe due to its multiple immune defects, the NOD mouse might not accurately reflect the immune status of the average prediabetic patient.