Inhibition of pro-inflammatory cytokine generation by CTLA4-Ig in the skin and colon of mice adoptively transplanted with CD45RBhi CD4+ T cells correlates with suppression of psoriasis and colitis.
Transfer of CD45RBhi CD4 + naïve T cells into severe combined immunodeficient (SCID) mice induces colitis and skin lesions. Recipients treated with cyclosporin A (CsA), CTLA4-Ig, or vehicle were evaluated for weight loss, skin lesions, and cutaneous blood flow. Necropsy, histological, hematological and cytokine analyses were performed at the conclusion of the experiment to confirm the clinical findings. Vehicle-treated mice lost weight and had 100% incidence of skin lesions by 46-days. CsA-treated mice also lost weight, but only 3/8 mice developed mild, clinically evident skin lesions. In contrast, all CTLA4-Ig-treated mice gained weight and did not develop skin lesions. Increase in cutaneous blood flow correlated with the development of skin lesions. Granulocyte numbers, which were high or moderately high in the vehicle- or CsA-treated mice, respectively, remained as low in the CTLA4-Ig-treated group as in untreated mice. IFN-gamma, IL-1beta, and TNF-alpha levels in the gut and skin correlated with the extent of inflammation in both organs. Histology revealed that CTLA4-Ig but not CsA effectively prevented both autoimmune disorders. The ability of CTLA4-Ig to prevent both colitis and skin lesions suggests that CD28-dependent co-stimulation of T cells is critical for generation of pro-inflammatory cytokines and induction of clinical disease in such autoimmune disorders.
Davenport
Colleen M
CM
Department of Immunology, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19406, USA. colleen_m_davenport@gsk.com
McAdams
Holly Ann
HA
Kou
Jen
J
Mascioli
Kirsten
K
Eichman
Christopher
C
Healy
Laura
L
Peterson
John
J
Murphy
Sreekant
S
Coppola
Domenico
D
Truneh
Alemseged
A
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology* / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D060908:CTLA-4 Antigen; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D017493:Leukocyte Common Antigens / Q000096:biosynthesis*; D051379:Mice; D016513:Mice, SCID; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D012867:Skin / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D017493:Leukocyte Common Antigens