Persistence of pathogenic CD4+ Th1-like cells in vivo in the absence of IL-12 but in the presence of autoantigen.
Despite recent successful treatment of murine autoimmune disease with anti-IL-12 mAb, it has not yet been addressed whether anti-IL-12 mAb can also be effective in late stages of disease and whether it can provide lasting protection against recurrence, especially during continued presence of autoantigen. We used a newly developed psoriasis model in scid/scid mice, which allows easy tracking of pathogenic T cells, to show that when anti-IL-12 mAb is given for 2 wk (1 mg/wk) in the late stage of severe disease, inflammation is greatly reduced, as measured by ear thickness and histology (scores, 1.1 +/- 0.1 vs 2.0 +/- 0.4). Moreover, prolonged treatment (4 wk) of chronic psoriatic mice with high doses of mAb (1 mg/wk; prolonged active anti-inflammatory treatment (PAAIT)) results in the almost complete resolution of lesions (scores, 0.3 +/- 0.1 vs 2.7 +/- 0.2). Surprisingly, however, despite these significant treatment results, the psoriasis-like lesions return soon after the anti-IL-12 mAb treatment is discontinued. This rapid relapse of disease may be attributed to large populations of activated CD4(+) T cells present in the lymph nodes of PAAIT animals still expressing an effector/memory phenotype (CD45RB(low), L-selectin(low)). Upon stimulation in vitro such PAAIT lymph node cells secrete high amounts of IFN-gamma (129 ng/ml); when transferred into naive scid/scid animals they are able to rapidly induce disease without costimulation. Our data indicates an alternative IL-12-independent pathway for pathogenic Th-1-like cells in vivo during the chronic phase of disease that allows these cells to persist and maintain their pathogenicity in the draining lymph tissue of the autoimmune site.
Protein Design Labs, Inc., Fremont, CA 94555, USA.
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Hong
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Berg
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Ehrhardt
D019264:Adoptive Transfer; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D001324:Autoantigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D002470:Cell Survival / Q000276:immunology; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D007115:Immunization Schedule; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011565:Psoriasis / Q000209:etiology / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D012008:Recurrence; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology* / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D001324:Autoantigens; D018664:Interleukin-12