Intervention of CD4+ cell subset shifts and autoimmunity in the BXSB mouse by murine CTLA4Ig.
In the BXSB autoimmune disease-prone mouse strain, male mice develop severe lupus-like symptoms and die early in life (4-6 mo), whereas females do not. We have previously demonstrated that profound phenotypic and functional changes occur with age in CD4+ cells from BXSB males. CD4+ cells from males (4 mo old) were predominantly CD44high, CD45RBlow, and MEL-14low (activated/memory phenotypes), while the reciprocal phenotypes characteristic of naive cells were prevalent in age-matched females and young adult males (2 mo old). CD4+ cells from older males proliferated less and produced less IL-2 and IFN-gamma than cells from either females or young males in response to immobilized anti-CD3 mAb. We tested the effect of CTLA4Ig treatment on the progression of disease in BXSB males. CD4+ cells from CTLA4Ig-treated mice at 4 mo of age were predominantly CD44low, CD45RBhigh, and MEL-14high phenotypes that were identical with those observed in CD4+ cells from young (3-mo-old) females. In contrast, control male mice treated with IgG2a accumulated the CD4+ memory phenotype. CD4+ cells from 4-mo-old male CTLA4Ig-treated mice proliferated and produced IL-2 at levels similar to those of cells from females in response to immobilized anti-CD3 mAb. Furthermore, in contrast to IgG2a-treated mice, female and CTLA4Ig-treated male mice at 4 mo of age produced no anti-chromatin Abs. Three of four male mice injected with CTLA4Ig until 6 mo of age appeared healthy at 8 mo of age, whereas all five of IgG2a-treated control males died by 6 mo of age. These 8-mo-old CTLA4Ig-treated males showed variable resistance to autoimmunity as well as function and phenotype marker expression, and a less striking glomerulonephritis than 4-mo-old untreated males. The results of this study demonstrate that the rampant T cell activation and T cell dysfunction that occur in male BXSB mice by 4 mo of age are abrogated by blocking the CTLA4-dependent costimulatory signal(s). They also show that treatment with CTLA4Ig can suppress the pathogenesis of disease and increase longevity.
Chu
E B
EB
Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
Hobbs
M V
MV
Wilson
C B
CB
Romball
C G
CG
Linsley
P S
PS
Weigle
W O
WO
D000069594:Abatacept; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D002843:Chromatin / Q000276:immunology; D005260:Female; D005921:Glomerulonephritis / Q000628:therapy; D018960:Hyaluronan Receptors / Q000032:analysis; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000145:classification / Q000627:therapeutic use; D007376:Interleukin-2 / Q000096:biosynthesis; D019041:L-Selectin / Q000032:analysis; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains
D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; D002843:Chromatin; C556707:Ctla4 protein, mouse; D018960:Hyaluronan Receptors; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007376:Interleukin-2; D019041:L-Selectin; D000069594:Abatacept; D017493:Leukocyte Common Antigens