CD40 ligand in pathogenesis of autoimmune ovarian disease of day 3-thymectomized mice: implication for CD40 ligand antibody therapy.
The blockade of CD40 ligand (CD40L) is effective in autoimmune disease prevention. Recently, a brief period of CD40L mAb treatment was reported to induce tolerance and enhancement of CD4(+)CD25(+) regulatory T cell activity. We therefore determined the efficacy of CD40L mAb treatment in autoimmunity that resulted from CD4(+)CD25(+) regulatory T cell deficiency. Autoimmune ovarian disease (AOD) and oocyte autoantibody response of day 3-thymectomized (d3tx) mice were inhibited by continuous CD40L mAb treatment from day 3, or from days 10-14, whereas CD40L mAb treatment confined to the neonatal week was ineffective. The enhanced expression of memory markers (CD44 and CD62L(low)) on CD4(+) T cells of the d3tx mice was unaffected by CD40L mAb treatment. In contrast, their increased T cell activation markers (CD69 and CD25) were eliminated by CD40L mAb treatment. Moreover, ex vivo activated T cells of d3tx mice expressed elevated intracellular IFN-gamma, and this was also blocked by CD40L mAb. The memory T cells, although nonpathogenic in CD40L mAb-positive environment, transferred severe AOD to CD40L mAb(-) neonatal recipients. Most importantly, CD40L mAb treatment inhibited AOD in recipients of T cells from d3tx donors with severe AOD and led to regression of AOD in d3tx mice documented at 4 wk. Therefore, 1) the continuous presence of CD40L mAb both prevents and causes regression of AOD in the d3tx mice; and 2) the multiple steps of the d3tx autoimmune disease, including T cell activation, cytokine production, T cell-mediated inflammation, and tissue injury, are CD40L dependent.
Sharp
Colin
C
Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
Thompson
Claire
C
Samy
Eileen T
ET
Noelle
Randolph
R
Tung
Kenneth S K
KS
D019264:Adoptive Transfer; D000818:Animals; D000831:Animals, Newborn; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D023201:CD40 Ligand / Q000276:immunology* / Q000502:physiology*; D005260:Female; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000276:immunology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D010049:Ovarian Diseases / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013934:Thymectomy
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D023201:CD40 Ligand; D007371:Interferon-gamma