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Proven Lupus Treatment By Dr Gary Levin

Proven Lupus Treatment System by Dr. Gary Levin

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Figure 5.9. (A) CD4 T cell depletion suppresses anti-dsDNA production. Thirty-three week-old NZB/W F1 mice were injected I.P. once with 500 |g with GK1.5, a depleting anti-CD4 mAb (gray triangles), rat IgG (inverted triangles), or left untreated, (filled squares). Anti-dsDNA serum antibodies were measured weekly. (B) CD8 T cells are not required for anti-CD137-mediated suppression of autoantibody production. Thirty-six week-old NZB/W F1 mice were injected I.P with 500 |g of YTS169.4, a depleting anti-CD8 mAb. One week later the mice were injected with 200 |g of anti-CD137 (filled squares) or left untreated (filled triangles) and serum anti-dsDNA antibodies measured every 5 days by ELISA.

If antibody producing, pathogenic B cells do have a short lifespan, one would expect to see a loss of autoantibody production as they die off.

Others have shown that anti-CD4 mAb mediated suppression or depletion of CD4 T cells causes a temporary loss of anti-dsDNA autoantibody production in NZB/W F1 mice and indicates the ever present need for CD4 T cell help in maintaining autoimmune disease (Wofsy, 1988, 1993; Wofsy etal., 1988; Wofsy and Seaman, 1985, 1987). This transient suppression is due to the removal of CD4 T cells followed by the clearance of anti-CD4 mAbs and the export of mature naive autoreactive CD4 T cells from the thymus (Figure 5.9A). Anti-CD137 non-depleting mAbs appear to affect the function of autoreactive CD4 T helper cells in maintaining autoantibody production, but whether this is a direct effect of anti-CD137 binding to autoreactive CD4 T cells or an indirect effect on their priming is not yet known.

We have found that injection of mice with anti-CD137 soon after LCMV infection suppressed anti-viral immunity in these mice. Dendritic cells in LCMV infected mice upregulate CD137 on their surface. DC taken from these mice display an immature phenotype, i.e., they had not upregulated CD40, CD80 or CD86 on their surface, phenotypic markers of DC maturation. Furthermore, in vitro crosslinking of CD137 on DC rapidly induced phosphorylation of Stat3, a negative

Figure 5.10. Autoimmune CD4 T cells reverse anti-CD137-mediated suppression of anti-dsDNA. Ten million CD4 T cells from 26 week-old autoimmune involved NZB/W F1 mice were injected I.V into recipients that had been injected three weeks earlier with anti-CD137 (filled triangles). A second group of mice that received anti-CD137 mAbs were injected with an isotype-matched control (filled squares). The mice were bled weekly and serum anti-dsDNA quantified by ELISA.

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Figure 5.10. Autoimmune CD4 T cells reverse anti-CD137-mediated suppression of anti-dsDNA. Ten million CD4 T cells from 26 week-old autoimmune involved NZB/W F1 mice were injected I.V into recipients that had been injected three weeks earlier with anti-CD137 (filled triangles). A second group of mice that received anti-CD137 mAbs were injected with an isotype-matched control (filled squares). The mice were bled weekly and serum anti-dsDNA quantified by ELISA.

regulator of DC and B cell maturation (Maris et al., submitted). These data suggest but do not conclusively prove that the immediate target of anti-CD137 mAbs in blocking SLE progression in lupus prone mice is the DC or other antigen presenting cells.

CD8 T cells in lupus-prone mice become activated and express CD137 as disease progresses, however, it appears that CD8 T cells play a minor role in controlling autoimmune disease in this setting and depletion of these T cells slightly exacerbates disease (our unpublished observations). However, CD8 T cell depletion does not affect the ability of anti-CD137 mAbs to induce suppression of anti-dsDNA autoantibodies (Foell et al., 2003; Figure 5.9b). Furthermore, suppressed CD4 T cell helper function in anti-CD137 treated mice can be overcome by adoptively transferring CD4 T cells from untreated 26 week-old lupus involved mice into the anti-CD137 treated mice after they have cleared most of the anti-CD137 mAb from their circulation (Figure 5.10).

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