Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 111, Issue 3, Pages 409-418Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200316090
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Funding
- NCRR NIH HHS [M01 RR000645, M01 RR00645] Funding Source: Medline
- NIAID NIH HHS [U19AI46132, U19 AI046132] Funding Source: Medline
- NIDDK NIH HHS [R01DK157846, P60 DK20595, P60 DK020595] Funding Source: Medline
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Dimeric Fc receptor (FcR) nonbinding anti-CD3 antibodies have been developed to minimize toxicities associated with classical anti-CD3 monoclonal antibodies (e.g., OKT3). Studies with murine analogs of non-FcR-binding antibodies have shown reduced mitogenicity compared to OKT3. in a trial of an FcR nonbinding humanized anti-CD3 mAb hOKT371(Ala-Ala) for treatment of patients with type I diabetes, we found significant increases in IL-10 and IL-5 in the serum of 63% and 72% of patients, respectively, and TNF-alpha and IL-6 levels that were lower than those previously reported following OKT3 therapy. The activation signal delivered by hOKT3gamma1 (Ala-Ala) was associated with calcium signaling and cytokine production by previously activated human cells in vitro. However, the production of IL-10, compared to IFN-gamma on a molar basis, was greater after culture with hOKT3gamma1(Ala-Ala) than with OKT3. Flow cytometric studies confirmed that OKT3 induced IFN-gamma and IL-10 production, but hOKT3gamma1(Ala-Ala) induced only detectable IL-10 production in CD45RO(+) cells. Moreover, in vivo, we found IL-10(+)CD4(+) T cells after drug treatment. These cells were heterogeneous but generally CD45RO(+), CTLA-4(-), and expressed CCR4. A subgroup of these cells expressed TGF-beta. Thus, the non-FcR binding anti-CD3 mAb, hOKT3gamma1 (Ala-Ala) delivers an activation signal to T cells that is quantitatively and qualitatively different from OKT3. It leads to the generation of T cells that might inhibit the autoimmune response and may be involved in the beneficial effect on beta cell destruction in Type 1 diabetes.
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