The Journal of Immunology, Vol 142, Issue 5 1470-1475, Copyright © 1989 by American Association of Immunologists

ARTICLES

Treatment of murine lupus with F(ab')2 fragments of monoclonal antibody to L3T4. Suppression of autoimmunity does not depend on T helper cell depletion

NL Carteron, CL Schimenti and D Wofsy
Immunology/Arthritis Section, Veterans Administration Medical Center, San Francisco, California 94121.

Treatment with mAb to the L3T4 Ag on Th cells can inhibit autoimmunity in mice. However, the mechanism by which anti-L3T4 inhibits autoimmunity is not known. In these studies, lupus-prone NZB/NZW F1 (B/W) mice were treated with F(ab')2 fragments of mAb to L3T4 to determine whether Th cell depletion is required for the beneficial effects of anti-L3T4. We first showed that treatment of female B/W mice with F(ab')2 anti-L3T4 from age 5 to 9 mo significantly reduced autoantibody production without depleting L3T4+ cells. However, treatment was complicated by the development of a host immune response to the rat mAb fragments. To circumvent this problem, female B/W mice were treated with a single high-dose of intact rat mAb to L3T4 (GK1.5) at age two mo. to induce immune tolerance to the mAb. Then, after recovery of L3T4+ cells, the mice were treated from age four to 14 mo with either F(ab')2 anti-L3T4 (0.5 mg 3 times per wk), intact anti- L3T4, or saline. In mice tolerized by this regimen, neither the F(ab')2 rat mAb nor the intact rat mAb elicited a host response. The mAb fragments bound target Ag but did not deplete the Th cells, whereas intact mAb to L3T4 profoundly depleted the L3T4+ cells. Despite this difference, both therapies had the same substantial beneficial effects on autoimmunity. They significantly decreased anti-DNA Ab production, improved renal function and prolonged survival. The initial tolerizing dose, by itself, did not inhibit autoimmunity. These findings show that anti-L3T4 suppresses autoimmunity by directly altering Th cell function through the L3T4 Ag, and not solely by depleting Th cells. They also document the detrimental effects of the host immune response to therapy with anti-L3T4 mAb, and they demonstrate a new strategy by which this response may be prevented.

This article has been cited by other articles:

				G.-J. Shim, L. L. Kis, M. Warner, and J.-A. Gustafsson Autoimmune glomerulonephritis with spontaneous formation of splenic germinal centers in mice lacking the estrogen receptor alpha gene PNAS, February 10, 2004; 101(6): 1720 - 1724. [Abstract] [Full Text] [PDF]

				E Keystone Treatments no longer in development for rheumatoid arthritis Ann Rheum Dis, November 1, 2002; 61(90002): ii43 - 45. [Full Text] [PDF]

				M. P. Reddy, C. A. S. Kinney, M. A. Chaikin, A. Payne, J. Fishman-Lobell, P. Tsui, P. R. Dal Monte, M. L. Doyle, M. R. Brigham-Burke, D. Anderson, et al. Elimination of Fc Receptor-Dependent Effector Functions of a Modified IgG4 Monoclonal Antibody to Human CD4 J. Immunol., February 15, 2000; 164(4): 1925 - 1933. [Abstract] [Full Text] [PDF]

				G G Illei and J H Klippel Novel approaches in the treatment of lupus nephritis Lupus, November 1, 1998; 7(9): 644 - 648. [Abstract] [PDF]

				Y. Shi, A. Kaliyaperumal, L. Lu, S. Southwood, A. Sette, M. A. Michaels, and S. K. Datta Promiscuous Presentation and Recognition of Nucleosomal Autoepitopes in Lupus: Role of Autoimmune T Cell Receptor alpha Chain J. Exp. Med., February 2, 1998; 187(3): 367 - 378. [Abstract] [Full Text] [PDF]