Generation and regulation of human Th1-biased immune responses in vivo: a critical role for IL-4 and IL-10.
Tissue damage in many human autoimmune diseases is mediated by activated autoantigen-specific Th1 cells. Delineation of the regulatory mechanisms controlling a Th1-biased human immune reaction and its pathologic potential is, therefore, a critical step in the understanding of autoimmune diseases. In this study, we introduce a novel means to investigate human Th1-biased immune responses in vivo. Intraperitoneal injection of human mononuclear cells into immunodeficient mice generates a xenogeneic Th1-biased human immune response characterized by systemic inflammation and leukocytic infiltrates with a granuloma-like architecture in the liver, and the perigastrointestinal and perirenal fatty tissue. Th1 cell activation was dependent on the presence of APCs and could be blocked by cyclosporine. Importantly, neutralization of endogenously produced IL-4 and IL-10 markedly exaggerated the immune response, whereas exogenous IL-4 and IL-10 inhibited systemic Th1 immunity. Thus, the model described in this paper presents a useful means to analyze the regulation of human immune reactions in an in vivo situation. The results suggest that both IL-4 and IL-10 contribute to controlling the development of a human Th1-biased immune reaction.
Skapenko
Alla
A
Nikolaus Fiebiger Center for Molecular Medicine, Clinical Research Group III, Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Niedobitek
Gerald U
GU
Kalden
Joachim R
JR
Lipsky
Peter E
PE
Schulze-Koops
Hendrik
H
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000637:transplantation; D015478:Antigens, Heterophile / Q000008:administration & dosage / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D016572:Cyclosporine / Q000008:administration & dosage; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016753:Interleukin-10 / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000637:transplantation; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000008:administration & dosage; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation
D015478:Antigens, Heterophile; D007166:Immunosuppressive Agents; D011994:Recombinant Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D016572:Cyclosporine