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Biomedical subjects

M K Racke

Publications and source records attributed to M K Racke.

46 records · Page 3Linked to original sources
PubMed1994

Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease.

The properties and outcome of an immune response are best predicted by the lymphokine phenotype of the responding T cells. Cytokines produced by CD4+ T helper type 1 (Th1) T cells mediate delayed type hypersensitivity (DTH) and inflammatory responses, whereas cytokines produced by Th2 T cells mediate helper T cell functions for antibody production. To determine whether induction of Th2-like cells would modulate an inflammatory response, interleukin 4 (IL-4) was administered to animals with experimental allergic encephalomyelitis (EAE), a prototypic autoimmune disease produced by Th1-like T cells specific for myelin basic protein (MBP). IL-4 treatment resulted in amelioration of clinical disease, the induction of MBP-specific Th2 cells, diminished demyelination, and inhibition of the synthesis of inflammatory cytokines in the central nervous system (CNS). Modulation of an immune response from one dominated by excessive activity of Th1-like T cells to one dominated by the protective cytokines produced by Th2-like T cells may have applicability to the therapy of certain human autoimmune diseases.

Animals↗
PubMed1994

T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis.

Encounters with antigen can stimulate T cells to become activated and proliferate, become nonresponsive to antigen, or to die. T cell death was shown to be a physiological response to interleukin-2-stimulated cell cycling and T cell receptor reengagement at high antigen doses. This feedback regulatory mechanism attenuates the immune response by deleting a portion of newly dividing, antigen-reactive T cells. This mechanism deleted autoreactive T cells and abrogated the clinical and pathological signs of autoimmune encephalomyelitis in mice after repetitive administration of myelin basic protein.

Animals↗
PubMed1994

Superantigen modulation of experimental allergic encephalomyelitis: activation of anergy determines outcome.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease that can be induced by the adoptive transfer of CD4, myelin basic protein (MBP)-specific T cells. Superantigens activate T cells expressing appropriate TCR V genes. In this study, MBP-specific T cells activated in vitro with a superantigen, staphylococcal enterotoxin B (SEB), could adoptively transfer a severe form of EAE in (PLxSJL)F1 mice, but did not transfer disease in PL/J or SJL/J mice. SEB treatment of donor mice anergized MBP-specific T cells using V beta 8 in (PLxSJL)F1 mice, because subsequent in vitro activation with SEB resulted in a marked decrease in proliferation to SEB and inability to transfer EAE. However, donor cells from (PLxSJL)F1 mice immunized with MBP/CFA that had been exposed to SEB in vivo before MBP stimulation in vitro still produced EAE in recipient mice. To confirm that non-V beta 8 T cells could transfer disease, donor mice were treated with antibody that eliminated V beta 8 T cells; MBP-activated T cells from these mice could still transfer EAE. Finally, EAE induced by SEB-activated T cells was substantially reduced in mice receiving anti-V beta 8 therapy in vivo. The ability of superantigens to activate encephalitogenic T cells may have relevance to human diseases such as multiple sclerosis.

Animals↗
PubMed1993

Cytokine-regulated adhesion between encephalitogenic T lymphocytes and cerebrovascular endothelial cells.

Adhesive interactions between murine cerebrovascular endothelial cells (EC) which comprise the blood-brain barrier (BBB) and myelin basic protein (MBP)-specific encephalitogenic T lymphocytes were investigated. Adhesion was assessed by measuring the percent attachment of 51Cr-labeled T cells to EC monolayers. The basal level adhesion (20-35%) was significantly up-regulated by treating EC with recombinant murine gamma interferon (IFN-gamma), interleukin-1 alpha (IL-1 alpha) and/or tumor necrosis factor-alpha (TNF alpha). The ability of these cytokines to modulate adhesion was dose- and time-dependent and could be detected as early as 1 h after treatment. The expression of intercellular adhesion molecule-1 (ICAM-1) by EC was examined by immunofluorescence staining and ELISA. Although all unstimulated EC cultures expressed ICAM-1, treatment of EC with the above cytokines dramatically up-regulated the level of ICAM-1 expression in a dose- and time-dependent fashion similar to that observed in the adhesion assays. Treatment of EC with transforming growth factor-beta 1 (TGF beta) down-regulated the level of T cell adhesion on untreated EC in a dose-dependent manner. Pretreatment of EC with TGF beta also partially inhibited the up-regulation of adhesion induced by IFN-gamma, IL-1 alpha and/or TNF alpha. TGF beta had no effect on the up-regulation of ICAM-1 expression induced by IFN-gamma, IL-1 alpha and/or TNF alpha. These results indicate that in addition to ICAM-1, other molecules may be involved in adhesion of encephalitogenic T cells to the EC comprising the cerebral vasculature.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Long-term treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 2.

It had been demonstrated previously that the administration of transforming growth factor-beta 1 (TGF-beta 1) reduced the clinical severity of experimental allergic encephalomyelitis (EAE). Treatment with the related immunosuppressive molecule, TGF-beta 2, resulted in similar inhibition of T cell activation and proliferation in vitro. Long-term treatment was effective in reducing clinical severity of EAE and the number of relapses in mice receiving either myelin basic protein- or peptide-91-103-specific T cell lines. When examined histologically, mice that had received TGF-beta 2 demonstrated significantly less inflammation and demyelination in the central nervous system. Examination of other organs demonstrated no pathology or deleterious side effects from long-term TGF-beta 2 therapy. These findings have relevance for the use of TGF-beta 2 as a therapeutic agent for the human demyelinating disease, multiple sclerosis.

Amino Acid Sequence↗
PubMed1992

Copolymer-1-induced inhibition of antigen-specific T cell activation: interference with antigen presentation.

Copolymer-1 (Cop-1) has been shown to inhibit in vivo development of experimental allergic encephalomyelitis (EAE) in animals and has been reported to have some therapeutic benefit in relapsing/remitting multiple sclerosis (MS). The mechanism by which Cop-1 acts in vivo is not known. The present study demonstrates that Cop-1 inhibits the in vitro response of several antigen-specific murine T cell hybridomas restricted to I-A, and to a lesser extent, I-E. The ability of human myelin basic protein (MBP)-specific T cell lines (TCL) to lyse targets in the context of three HLA-DR types associated with MS was also impaired by Cop-1. The results suggest that the observed inhibition was due to competition between Cop-1 and nominal antigen for the class II major histocompatibility complex (MHC) peptide binding site.

Animals↗
PubMed1992

Evidence of endogenous regulatory function of transforming growth factor-beta 1 in experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterized by inflammation and demyelination in the central nervous system (CNS). Administration of transforming growth factor-beta (TGF-beta) has been shown to inhibit EAE. In this study, the possible role of endogenous TGF-beta in the regulation of relapsing EAE produced by the transfer of myelin basic protein-specific T cell lines was assessed. Although TGF-beta is not present in the normal CNS, this cytokine was detected by immunohistology in areas of central nervous system inflammation in both acute and chronic disease. The administration of anti-TGF-beta at the disease onset led to a worsening of the clinical course of EAE and more extensive pathological lesions. These findings provide direct evidence for a role of endogenous TGF-beta in the remissions seen in chronic relapsing EAE.

Animals↗
PubMed1991

Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 1.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterized by inflammation and demyelination in the central nervous system. The effect of the immunosuppressive molecule transforming growth factor-beta, (TGF-beta 1) on chronic relapsing EAE produced by the transfer of myelin basic protein-specific T cell lines was studied. TGF-beta 1 markedly inhibited the activation and proliferation of myelin-basic protein-specific lymph node cells in vitro. This reduced the capacity of these cells to transfer EAE. In addition, administration of TGF-beta 1 in vivo consistently resulted in an improved clinical course, even when given during ongoing disease. Immunopathologic study demonstrated a marked reduction in central nervous system damage and expression of cell-surface lymphocyte function-associated Ag-1 and class II MHC molecules in TGF-beta 1-treated mice. These findings have identified TGF-beta 1 as a possible therapeutic agent for the human demyelinating disease multiple sclerosis.

Animals↗