A key target for novel stroke therapy is the regulation of post-ischemic inflammatory mechanisms. Recent evidence emphasizes the role of T lymphocytes of differing subtypes in the evolution is ischemic brain damage. We have recently demonstrated the benefit of myelin antigen-specific immunodulatory agents known as recombinant T cell receptor ligands (RTLs) in a standard murine model of focal stroke. The aim of the current study was to extend this initial observation to RTL treatment in a therapeutically relevant timing after middle cerebral artery occlusion (MCAO) and verify functional benefit to complement histological outcome measures. We observed that the administration of mouse-specific RTL551 reduced infarct size and improved sensorimotor outcome when administered within a 3 h post-ischemic therapeutic window. RTL551 treatment reduced cortical, caudate putamen, and total infarct volume as compared to vehicle-treated mice. Using a standard behavioral testing repertoire, we observed that RTL551 reduced sensorimotor impairment 3 days after MCAO. Humanized RTL1000 (HLA-DR2 moiety linked to hMOG-35-55 peptide) also reduced infarct size in HLA-DR2 transgenic mice. These data indicate that this neuroantigen-specific immunomodulatory agent reduces damage when administered in a therapeutically relevant reperfusion timeframe.

01 May 1995·European Journal of ImmunologyQ3 · MEDICINE

Suppression of experimental autoimmune encephalomyelitis in Lewis rats by antibodies against CD2

Q3 · MEDICINE

Article

Author: Stefan Jung ; Klaus Toyka ; Hans‐Peter Hartung

AbstractThe immunotherapeutic potential of three anti‐rat CD2 monoclonal antibodies (mAb) (OX34, OX54, OX55) and the combination of OX54 with OX55 was tested in Lewis rat experimental autoimmune encephalomyelitis (EAE). In actively induced EAE, a single injection of OX34 2 days before immunization with myelin basic protein (MBP) in complete Freund's adjuvant (CFA) completely prevented or greatly attenuated EAE in all animals. Injection of OX54 acted moderately suppressive while OX55 or OX54/55 did not affect disease severity. Abrogation of EAE by OX34 was not restricted to its application before immunization. Therapeutic administration of all three mAb and the Ab combination from onset of first clinical signs efficiently blocked progression of disease and prevented all animals from developing hind limb paresis. In adoptive transfer EAE induced with in vitro activated cells of an encephalitogenic T helper line, clinical and histological signs were completely prevented by injection of OX34 on the day of cell transfer and 4 days later, underlining the strong impact of anti‐CD2 mAb on the effector phase of disease.Immunocytofluorometric analysis of peripheral blood lymphocytes after a single Ab injection demonstrated that all mAb induced a variable degree of transient reduction in T cell numbers and modulation of CD2 antigens. In contrast to the other mAb, OX34 persisted on lymphocytes for at least 11 days, which may explain its unique suppressive effect on EAE after a single injection before immunization. The assumption that prophylactic administration of OX34 also inhibits MBP‐induced EAE, due to persistence into the effector phase, was substantiated by the finding that none of the mAb prevented generation of an antigen‐specific cellular response in MBP/CFA‐immunized animals. Since none of the Ab induced T cell unresponsiveness or inhibited T cell activation by antigen‐ or Ab‐mediated stimulation of the T cell receptor, we suggest that their marked action on the effector phase of EAE may rely on inhibition of T cell infiltration into the central nervous system. The demonstrated efficacy of these anti‐CD2 mAb in EAE suggests a potential therapeutic role that may be equal to that of anti‐CD4 or anti‐T cell receptor Ab.

01 Nov 1994·European Journal of ImmunologyQ3 · MEDICINE

Transfer of Sjögren's syndrome‐like autoimmune lesions into SCID mice and prevention of lesions by anti‐CD4 and anti‐T cell receptor antibody treatment

Q3 · MEDICINE

Article

Author: Norio Haneji ; Kumiko Yanagi ; Yoshio Hayashi ; Hironori Hamano

AbstractWe describe the successful transfer of murine Sjögren's syndrome‐like autoimmune lesions from MRL/lpr mice (H‐2k) to severe combined immunodeficiency (SCID) mice (H‐2d) and prevention of lesions by anti‐CD4 and ‐T cell receptor Vβ8 antibody treatment. Mononuclear cells (1 × 106) isolated from the inflammed submandibular salivary gland tissues of MRL/lpr mice were transferred intraperitoneally into SCID mice. Autoimmune lesions resembling those seen in Sjögren's syndrome developed in the salivary and lacrimal glands of SCID mice 8 weeks after the injection, whereas other organs did not show any lesion. This pathology resembles Sjögren's syndrome in humans involving both the salivary and lacrimal glands. Immunohistochemically, a major proportion of these infiltrating cells in transferred SCID mice were CD4+ and Vβ8+. When the spleen cells from MRL/lpr mice were injected, severe inflammatory lesions, probably resulting from a graft‐versus host reaction, were observed in multiple organs of SCID mice. The disease could not be induced by intraperitoneal administration of the sera from MRL/lpr mice, or of the spleen cells from C3H/He (H‐2k) and BALB/c (H‐2d) mice. We detected autoantibody production specific for the salivary gland tissue in sera from transferred SCID mice. Moreover, we found that the lesions were prevented by administration of the isolated cells treated in vitro with anti‐CD4 and anti‐Vβ8 monoclonal antibodies. These results suggest that CD4‐ and Vβ8‐bearing T cells are involved in recognizing an autopeptide and triggering autoimmunity in the salivary and lacrimal glands, and therapies designed with anti‐CD4 and anti‐Vβ8 antibodies may prove effective in treating the murine autoimmune disease.

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