Persistence of pathogenic CD4+ Th1-like cells in vivo in the absence of IL-12 but in the presence of autoantigen.

Abstract

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.

• Authors: K Hong, E L Berg, R O Ehrhardt
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 166 Issue 7 Pg. 4765-72 (Apr 01 2001) ISSN: 0022-1767 [Print] United States
• PMID: 11254739 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antibodies, Monoclonal
• Autoantigens
• Interleukin-12

Topics

• Adoptive Transfer
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage)
• Antibodies, Monoclonal (administration & dosage, therapeutic use)
• Autoantigens (physiology)
• CD4-Positive T-Lymphocytes (immunology, pathology, transplantation)
• Cell Survival (immunology)
• Chronic Disease
• Disease Models, Animal
• Female
• Immunization Schedule
• Injections, Intraperitoneal
• Interleukin-12 (antagonists & inhibitors, deficiency, immunology)
• Lymph Nodes (immunology, pathology, transplantation)
• Lymphocyte Depletion
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Psoriasis (etiology, immunology, pathology, therapy)
• Recurrence
• T-Lymphocyte Subsets (immunology, pathology, transplantation)
• Th1 Cells (immunology, pathology)