Presented at:
2005 Meeting of the Federation of Clinical Immunology Societies, Boston, MA, May 12-16, 2005.
Immune monitoring: the effects of hOKT3γ1(Ala-Ala) in a patient with new onset type 1 diabetes mellitus
Liu WH, Szot G, Earle KE, Herold KC, Masharani U, Gitelman SE, Bluestone JA
Diabetes Center, University of California at San Francisco, San Francisco, CA; Department of Medicine, University of California at San Francisco, San Francisco, CA; Naomi Berrie Diabetes Center, Columbia University, New York, NY; Department of Pediatrics, University of California at San Francisco, San Francisco, CA.
Background: Type1 diabetes (TID) is an autoimmune disease caused by the pathogenic action of T lymphocytes which destroy insulin producing beta cells. An effective immunomodulatory anti-CD3 antibody, hOKT3γ1(Ala-Ala), used to treat new onset TIDM had direct effects on pathogenic T cells and induced regulatory cells.
Methods: In a Phase II trial sponsored by the Immune Tolerance Network, we studied the effects of the hOKT3γ1(Ala-Ala) on immune responses in patients with new onset TID. Six patients were treated with hOKT3γ1(Ala-Ala) I.V. daily for 12 days. Immunophenotyping; T cell proliferation by CFSE-based flow cytometry; and cytokine secretion were performed.
Results: Transient depletion of T cells in patients followed by recovery of the cells after the 12 day antibody course was observed in all but one patient who demonstrated a prolonged reduction in the number of circulating CD4+ T cells. Nine months after therapy, the patients CD4 count was 102x106/mL and did not return to normal levels till 29 months post therapy (512 x 106/ml). In contrast, the CD8+ T cell count recovered rapidly and reached 86% of baseline by 30 days. No obvious difference in either coating or modulation of CD3 on T cells was observed on the CD4+ T cells as compared to the other treated individuals. Trough levels of drug were higher but not exceptionally different than observed in the majority of treated individuals. However, there was selective recovery of CD45RO cells and CD4+CD62L+CD25hi Treg population increased during the treatment. In spite of the reduced CD4+ Tcell count, the T cells functioned normally on a per cell basis as demonstrated by CFSE proliferation and IL-2 secretion. Clinically, the patient had an uneventful clinical course with only a transient viral syndrome shortly after treatment, with all cultures and serological studies negative. The patient was maintained on anti-microbial prophylaxis until her CD4+ count recovered. The patients c-peptide levels remain high at 2 years (77% of baseline) while maintaining a normal Hemoglobin A1c at 18 months comparable to that noted in other responders.
Discussion: In the present clinical study of hOKT3γ1 (Ala-Ala) one patient experienced a prolonged decrease in CD4+ T cells. The therapy did not lead to impaired CD4 function ex vivo, or to opportunistic infections. The unremarkable clinical course may relate to lack of depletion centrally, and/or failure to cause more generalized immunosuppression.Since the higher circulating levels did not result in a better clinical response, the data support dosing at the previous lower phase I/II levels helping define the window for safety and efficacy with this agent.