Abstract | Investigators | Background | Resources

Both psoriasis and PsA are associated with specific MHC Class I alleles. Analysis of synovial fluid from PsA patients reveals an increase in CD8+ T lymphocytes and cytokine expression in the synovium is consistent with a Th1-type response. Furthermore, autologous reconstitution of SCID mice transplanted with uninvolved skin from psoriasis patients with lymphocyte subsets indicates that both peripheral CD4+ and intradermal CD8+ cells are required to induce psoriasis. These observations indicate that therapeutic stategies which target Th1 cells may be efficacious in the treatment of psoriasis and the associated arthritis. Non-FcR binding anti-CD3 antibodies have been shown to preferentially anergize Th1 and stimulate Th2 lymphocytes. To repolarize peripheral T cells, repeated rounds of stimulations are usually required.

In a phase I/II trial, hOKT3γ(Ala-Ala) was given to eight patients with PsA who had failed at least one remittive agent. The monoclonal antibody was given as a daily infusion for up to 14 days with a variable escalation of dose to a maximum of 4 mg. Of the seven patients who completed the trial, six had dramatic improvement in their tender and swollen joint counts. Indeed, 5 of 6 had no swollen joints at 30 days. Symptoms from hOKT3γ(Ala-Ala) were mild when given as an escalating dose. Emesis and fevers occured in one patient receiving an initial maximum dose.

We now propose a phase II/III blinded placebo controlled trial to demonstrate the safety and efficacy of hOKT3γ(Ala-Ala) in the treatment of PsA. Based on previous mechanistic studies and clinical experience, we postulate that hOKT3γ(Ala-Ala) will induce remission in patients by selectively anergizing Th1 populations. We will recruit 112 patients failing Methotrexate at seven academic centers and administer either antibody with a rapid dose escalation or placebo daily for 5 days once every 4 weeks for 4 cycles total. Patients will be followed for one year.

Mechanistic Studies: To complement the clinical trial, we propose an extensive array of mechanistic studies to address several questions including:

1. Does hOKT3γ(Ala-Ala) selectively induce the anergy of pathogenic Th1 cells in vivo?
2. Are other changes in T cell populations induced by hOKT3γ(Ala-Ala)?
3. Can specific gene products be identified which are either required for or predict angery?

The completion of the proposed investigations will determine the efficacy and in vivo immunomodulatory effects of a non-mitogenic anti-CD3 antibody in the treatment of a chronic T cell-mediated autoimmune disease. Preliminary evidence indicates that such treatment will preferentially induce anergy in Th1 populations leading to drug free remission in some patients.

Participating Investigators

	Marcus Clark, University of Chicago
	Brian Kotzin, University of Colorado
	Kathryn Hobbs, University of Colorado
	Brian Nickoloff, Loyola University
	John Davis, University of California San Francisco
	Kenneth Kalunian, University of California Los Angeles
	Wayne Yokoyama, Washington University
	Richard Brasington, Washington University
	Daniel Albert, University of Pennsylvania
	Sharon Kolasinski, University of Pennsylvania
	Robert Ike, University of Michigan
	Mariana Kaplan, University of Michigan
	Louis Heck, University of Alabama

Background Articles

	Current concepts in psoriatic arthritis - Curr Opin Rheumatol [go]
	hOKT3γ(Ala-Ala) delivers partial TCR signal - J Immunol [go]
	Modified anti-CD3 therapy in psoriatic arthritis - J Rheumatol [go]

Resources & Interesting Links

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