Targeting T cell-specific costimulators and growth factors in a model of autoimmune hemolytic anemia.
Although it is established that failure of regulatory mechanisms underlies many autoimmune diseases, the stimuli that activate autoreactive lymphocytes remain poorly understood. Defining these stimuli will lead to therapeutic strategies for autoimmune diseases. IL-2-deficient mice develop spontaneous autoimmunity, because of a deficiency of regulatory T cells, and on the BALB/c background, they rapidly die from autoimmune hemolytic anemia. To define the importance of costimulatory pathways in various components of this autoimmune disorder, we first intercrossed IL-2-deficient mice with mice lacking CD28 or CD40L. Elimination of CD28 reduced the activation of autoreactive T cells and lymphoproliferation as well as production of autoantibodies, whereas elimination of CD40L reduced autoantibody production without affecting T cell expansion and accumulation. To examine the role of IL-7, we blocked IL-7R signaling with neutralizing Abs. This treatment inhibited the production of autoantibodies and the development of autoimmune hemolytic anemia. Together, these data indicate that specific costimulatory and cytokine signals are critical for the spontaneous autoantibody-mediated disease that develops in IL-2-deficient mice.
Hoyer
Katrina K
KK
Department of Pathology, University of California-San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA.
Wolslegel
Kristen
K
Dooms
Hans
H
Abbas
Abul K
AK
D000744:Anemia, Hemolytic, Autoimmune / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001323:Autoantibodies / Q000097:blood; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D007376:Interleukin-2 / Q000235:genetics; D015851:Interleukin-7 / Q000037:antagonists & inhibitors / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors / Q000502:physiology
D000906:Antibodies; D001323:Autoantibodies; D018106:CD28 Antigens; D036341:Intercellular Signaling Peptides and Proteins; D007376:Interleukin-2; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; D023201:CD40 Ligand