T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination

Abstract

Experimental allergic encephalomyelitis (EAE) serves as a model for autoimmune diseases mediated by T lymphocytes. Following sensitization to rat, mouse or guinea pig myelin basic protein (MBP) in complete Freund's adjuvant, inbred mouse strains PL/J (H-2u), SJL/J (H-2s) and (PL/J X SJL/J)F1((PLSJ)F1) develop EAE. Whereas sensitization to the N-terminal 37 amino-acid peptide of rat or guinea pig MBP [MBP(1-37)] induces EAE in PL/J mice, immunization to the C-terminal peptide (89-169) leads to EAE in SJL/J mice. The immune response to MBP in (PLSJ)F1 mice is not co-dominant; sensitization to the N-terminal peptide induces EAE, while sensitization to the C-terminal peptide does not. We have generated MBP-specific T-cell clones restricted to class II (Ia) antigens of the major histocompatibility complex (MHC) from PL/J and (PLSJ)F1 mice following sensitization to rat MBP. Two such I-Au-restricted T-cell clones that proliferate in response to the encephalitogenic N-terminal MBP peptide and recognize a shared determinant with mouse (self) MBP cause paralysis in 100% of (PLSJ)F1 mice tested. Paralysis is induced even when recipients are injected with as few as 1 X 10(5) cloned T cells. Relapsing paralysis followed in two-thirds of the recipients after recovery from acute paralysis, whereas one-third developed chronic persistent paralysis, a form of EAE not usually seen. Histopathology revealed intense perivascular inflammation, demyelination and remyelination within the central nervous system of paralysed mice. The experimental disease induced with these clones shares important features with human demyelinating diseases such as multiple sclerosis. This is the first demonstration that T-cell clones that respond to a defined self-antigen can induce clinical and histological autoimmune disease.

Inflammatory cells, microglia and MHC class II antigen-positive cells in the spinal cord of Lewis rats with acute and chronic relapsing experimental autoimmune encephalomyelitis

“…In mice, immunocytochemical studies demonstrated CD4 + T cells in the CNS in relapses of CR-EAE (Traugott et al, 1986;Baker et al, 1990) and radio-labelling has demonstrated passively transferred cells in the nervous system, especially in perivascular cuffs, in CR-EAE in SJL/J mice (Cross et al, 1990). These studies, together with the present study which clearly demonstrates an influx of CD4 + T cells into the CNS in the second episode of CR-EAE, suggest that CD4 + T cells, the effector cells in acute EAE (Pettinelli and McFarlin, 1981;Zamvil et al, 1985), continue to be important in relapses of CR-EAE.…”

Demyelination and early remyelination in experimental allergic encephalomyelitis passively ransferred with myelin basic protein-sensitized lymphocytes in the Lewis rat

“…The preferential involvement of the spinal roots with sparing of the peripheral nerves may be due to the reduced blood-nerve barrier in the roots (Olsson, 1968) and the almost 3-fold higher concentration of P 1 in the spinal root than in the peripheral nerve in the rat (Greenfield et al, 1973). In mice, CNS demyelination has been described in EAE passively transferred by MBP-specific lymph node cells, T cell lines and T cell clones (Raine et al, 1984;Zamvil et al, 1985;Tabira and Sakai, 1987) and in EAE passively transferred by proteolipid-protein-specific T cell lines (Satoh et al, 1987). The reported sparing of the PNS in mice with passively transferred MBP-EAE (Raine et al, 1984;Tabira and Sakai, 1987) could be due to interspecies differences in the blood-nerve barrier, Ia antigen expression, or MBP concentration in the spinal roots or to differences in MBP epitopes in intact CNS and PNS myelin in the mouse.…”

“…Passive EAE was originally induced by the direct transfer of lymph node cells from animals sensitized to whole spinal cord (Paterson, 1960). More recently, techniques have been described for the in vitro augmentation of donor lymphocyte activity (Panitch and McFarlin, 1977;Richert et al, 1979), and these have ultimately led to the development of MBP-specific T cell lines and clones which are capable of transferring disease in low doses (Ben-Nun et al, 1981;Ben-Nun and Cohen, 1982;Zamvil et al, 1985). EAE, either actively or passively induced, may have an acute or a chronic relapsing course, but each form produces the same neurological signs, namely tail paralysis and limb ataxia, weakness and paralysis.…”

The gray aspects of white matter disease in multiple sclerosis

“…3, demonstrated that T cell lines could induce EAE (14). Specific T cell clones were then produced that could induce relapses and remissions characteristic of early MS (15). Now inbred animals carrying the T cell receptors for such clones have been genetically engineered, making it possible to take a programmed mouse off the rack, which will get EAE spontaneously (16).…”