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.
Hong
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K
Protein Design Labs, Inc., Fremont, CA 94555, USA.
Berg
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Ehrhardt
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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