Induction of Th2 cytokines and control of collagen-induced arthritis by nondepleting anti-CD4 Abs.
CD4+ T cells play a key role in the development of cell-mediated autoimmune diseases, and their modulation has been used to prevent autoimmune diseases in animal models. The effect of the nondepleting anti-CD4 mAb (KT6) was investigated in collagen-induced arthritis (CIA) in DBA/1 mice and in adoptive transfer of CIA into SCID mice. KT6 (200 microg/dose/mouse) was administered systematically from the day of collagen type II (CII) immunization and continued by alternate-day injection until day 11. Only 20% of KT6-treated mice developed arthritis compared with 100% of the isotype control treated mice (p < 0.001). KT6 treatment in a similar regimen also abrogated the adoptive transfer of CIA into SCID mice. Serum levels of IgG2a anti-CII Abs in KT6-treated DBA/1 mice were significantly reduced (p < 0.001), while IgG1 anti-CII were not significantly changed (p > 0.05). Lymph node cells of mice treated in vivo with KT6 had a reduced production of IFN-gamma but increased IL-4 upon in vitro challenge with CII. Furthermore, KT6 could also reverse the profile of cytokine release of in vivo primed and pathogenic CII-specific T cells. These results demonstrate that in vivo modulation with nondepleting anti-CD4 Abs prevents CIA, likely by altering the functional profile of Th1 T cells to Th2. Furthermore, we demonstrate that this treatment can not only prevent, but more importantly also control pathogenic T cells by switching their cytokine production from a Th1 to a Th2-like profile. Our results thus provide compelling evidence of how treatment with nondepleting anti-CD4 may control an autoimmune process. They also indicate that this approach not only prevents, but also could control ongoing autoimmune diseases.
Chu
C Q
CQ
Kennedy Institute of Rheumatology, London, United Kingdom.
Londei
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000209:etiology* / Q000276:immunology / Q000517:prevention & control*; D015704:CD4 Antigens / Q000276:immunology*; D003094:Collagen; D016207:Cytokines / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000187:drug effects; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008212:Lymphocyte Depletion; D051379:Mice; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016207:Cytokines; D015847:Interleukin-4; D007371:Interferon-gamma; D003094:Collagen