Prevention and treatment of murine experimental allergic encephalomyelitis with T cell receptor V beta-specific antibodies.

Abstract

Experimental allergic encephalomyelitis (EAE)' is an autoimmune disease of the central nervous system (CNS) that is induced by immunization of susceptible animal strains with myelin basic protein (MBP). The disease is characterized by lymphocyte infiltration leading to CNS lesions, demyelination, and chronic relapsing paralysis, which are symptoms similar to those seen for multiple sclerosis (MS) in humans (1-6). Prevention of EAE by treatment with CD4-specific antibodies (7,8) and adoptive transfer of disease symptoms with MBP-specific T helper (Th) cells (9-16) have implicated CD4+ Th cells as the primary disease-inducing component of EAE.The dominant T cell response to MPB in mice of particular MHC haplotypes is directed towards distinct MBP determinants (16)(17)(18)(19)(20). For example, B10.PL and PL/J mice (H-2°) respond primarily to an acetylated NH2-terminal epitope, while SJL/J mice (H-2g) respond primarily to a more COOH-terminal epitope. Recent studies have indicated that in H-2u mice the T cell response to the dominant NH2-terminal epitope of MBP is of limited heterogeneity (21-23). Molecular characterization of the TCRs used by B10.PL-derived Th cells revealed the use of only two distinct V/3 gene segments, V/38.2 and VS13, and two distinct Va gene segments, Va2.3 and Va4.3 (21). The gene products of either V/3 segment can pair with the gene products ofeither Va segment to yield a total of four discrete types ofTh cells. The majority of Th cells examined expressed the V08.2 gene segment (84%) while the remainder expressed the V013 gene segment (16%). The distribution ofVa gene segments was less skewed among these MBP-specific Th cells with 60% expressing Va2 .3 and 40% expressing Va4.3 .The limited use of TCR V region genes in the response to MBP allows the application of unique strategies of specific immune intervention . Since the majority of MBP NH2-terminal reactive Th cells in H-2u mice use V08.2, mAbs to V08 (F23 .1,

Inhibition of Experimental Allergic Encephalomyelitis with an Antibody that Recognizes a Novel Antigen Expressed on Lymphocytes, Endothelial Cells, and Microglia

“…Several lines of evidence support our contention. Similar to this study using TLD-4A2 mAb, several earlier reports have demonstrated EAE inhibition using purified mAb against a series of immunologically important molecules including: MHC class II molecules (Sriram and Steinman, 1983;Steinman et al, 1981), the T cell receptor (Zaller et al, 1990), CD4, ICAM-1 (Archelos et al, 1993), VLA-4 (Baron et al, 1993;Kent et al, 1995;Yednock et al, 1992) CR3 (Huitinga et al, 1993), CD28 , and the CD40L (gp39) (Gerrotse et al, 1996). Yet all of these other molecules have molecular weights, cellular distributions, and flow cytometry profiles distinct from the 4A2 molecule.…”

“…mAb to interfere with T cell/endothelial cell or T cell/APC interactions and thereby block EAE induction (Baron et al, 1993;Brostoff and Mason, 1984;Kent et al, 1995;Sloan et al, 1992;Sriram and Roberts, 1986;Sriram and Steinman, 1983;Yednock et al, 1992;Zaller et al, 1990). With notable exceptions, few studies have investigated the mechanism(s) by which this EAE inhibition occurred (Bauer et al, 1995;Kent et al, 1995;Yednock et al, 1992).…”

“…The central role of these cells is demonstrated by studies employing monoclonal antibodies directed against a wide variety of molecules expressed on the surface of T lymphocytes and macrophages. Such treatment interferes with the function or migration of these cells, and blocks the initiation and development of EAE (Brosnan et al, 1981;Brostoff and Mason, 1984;Huitinga et al, 1990Huitinga et al, , 1993Sriram and Steinman, 1983;Zaller et al, 1990). At this time, the exact parameters governing lymphocyte and macrophage traffic into the human CNS, as occurs in MS, are incompletely defined.…”

TCR usage and cytokine expression in peripheral blood and BAL T cells

“…There is evidence from murine models of asthma that T cell subsets bearing different Vb chains show differences in their cytokine production, which in turn may lead to functional differences of the T cell subpopulations [16,17]. A similar observation has been made in experimental allergic encephalomyelitis in the mouse, where the pathological response can be modulated by using monoclonal antibodies to eliminate particular T cell subpopulations [18]. We hypothesized that human blood and BAL T cell subsets bearing various TCR-Vb genes might show selective differences in their cytokine profile compared to one another and to the overall T cell population.…”

Analysis of T cell receptor Vα and Vβ gene usage in synovia of patients with rheumatoid arthritis

“…It is feasible that QRRAA at positions 70-74 ofthe HLA-DRpi T cells with a distinct antigen specificity express, molecule, a region involved in T cell recognition in terms of V gene usage, a restricted Tcr reper- (4) toire. This could possibly be a target site for A characteristic feature ofthe rheumatoid specific immune intervention in human autoimsynovium is an intense lymphoeytie infiltration mune disease, if particular receptors are indeed (5) consisting mainly of T cells which express involved in the development of autoimmunity, class II MHC antigens (6), CD4 (7) animal model of human multiple sclerosis, by vaccination with monoclonal antibodies directed against specific Tcr Vp chains (13).…”