IL‐12 directs severe renal injury, crescent formation and Th1 responses in murine glomerulonephritis

Glomerular crescent formation characterizes severe glomerulonephritis (GN). Evidence suggests that crescent formation results from a delayed‐type hypersensitivity‐like Th1 response. As IL‐12 directs Th1 responses, we tested the hypothesis that IL‐12 is important in crescentic GN. Neutralization of IL‐12 attenuated crescent formation and cell‐mediated injury in C57BL/6 mice sensitized to and challenged with sheep anti‐mouse glomerular basement membrane (GBM) globulin. Recombinant IL‐12 induced severe crescentic GN with enhanced Th1 responses in C57BL/6 mice in which non‐crescentic GN was induced by injecting anti‐GBM globulin into naive mice. BALB/c mice do not develop significant crescent formation in these models, due either to regulatory effects of IL‐4, or to deficits in IL‐12 production/responsiveness. Administering IL‐12 to BALB/c mice with GN induced Th1 responses and crescent formation, whereas IL‐4‐deficient BALB/c mice did not develop cell‐mediated crescentic injury when GN was induced in sensitized mice. These results establish a central role for IL‐12 in severe crescentic GN.

[1]  J. Hoxie,et al.  Construction of single‐chain antibodies that bind an overlapping epitope of HIV‐1 Nef , 1998, FEBS letters.

[2]  J. O'brien,et al.  Prosaptide activates the MAPK pathway by a G-protein-dependent mechanism essential for enhanced sulfatide synthesis by Schwann cells. , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  R. Kalluri,et al.  Susceptibility to anti-glomerular basement membrane disease and Goodpasture syndrome is linked to MHC class II genes and the emergence of T cell-mediated immunity in mice. , 1997, The Journal of clinical investigation.

[4]  I. Müller,et al.  Characterization of T cell-mediated responses in nonhealing and healing Leishmania major infections in the absence of endogenous IL-4. , 1997, Journal of immunology.

[5]  P. Tipping,et al.  Th2 responses induce humorally mediated injury in experimental anti-glomerular basement membrane glomerulonephritis. , 1997, Journal of the American Society of Nephrology : JASN.

[6]  K. Murphy,et al.  Genetic control of Interleukin 12 responsiveness: implications for disease pathogenesis , 1997, Journal of Molecular Medicine.

[7]  P. Tipping,et al.  Interleukin-4 and interleukin-10 attenuate established crescentic glomerulonephritis in mice. , 1997, Kidney international.

[8]  J. Louis,et al.  Early production of IL-4 in susceptible mice infected with Leishmania major rapidly induces IL-12 unresponsiveness. , 1997, Journal of immunology.

[9]  S. Szabo,et al.  Regulation of the Interleukin (IL)-12R β2 Subunit Expression in Developing T Helper 1 (Th1) and Th2 Cells , 1997, The Journal of experimental medicine.

[10]  P. Tipping,et al.  Antibody independent crescentic glomerulonephritis in mu chain deficient mice. , 1997, Kidney international.

[11]  P. Tipping,et al.  Immune modulation with interleukin‐4 and interleukin‐10 prevents crescent formation and glomerular injury in experimental glomerulonephritis , 1997, European journal of immunology.

[12]  Kenneth M. Murphy,et al.  Functional diversity of helper T lymphocytes , 1996, Nature.

[13]  M. Daly,et al.  Genetic mapping of a murine locus controlling development of T helper 1/T helper 2 type responses. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[14]  D. Carvajal,et al.  IL-12-Deficient Mice Are Defective in IFNγ Production and Type 1 Cytokine Responses , 1996 .

[15]  S. Reed,et al.  CD40 ligand is required for protective cell-mediated immunity to Leishmania major. , 1996, Immunity.

[16]  I. Müller,et al.  Susceptibility to Leishmania major Infection in Interleukin-4-Deficient Mice , 1996, Science.

[17]  W. Dietrich,et al.  Genetic Susceptibility to Leishmania: IL-12 Responsiveness in TH1 Cell Development , 1996, Science.

[18]  D. Baker,et al.  Genetic analysis of experimental allergic encephalomyelitis in mice. , 1995, Journal of immunology.

[19]  D. Postma,et al.  Genetic susceptibility to asthma--bronchial hyperresponsiveness coinherited with a major gene for atopy. , 1995, The New England journal of medicine.

[20]  L. Adorini,et al.  The role of IL-12 in the induction of organ-specific autoimmune diseases. , 1995, Immunology today.

[21]  G. Trinchieri,et al.  IL-12 is required for natural killer cell activation and subsequent T helper 1 cell development in experimental leishmaniasis. , 1995, Journal of immunology.

[22]  G. Trinchieri,et al.  Interleukin‐12 is required for interferon‐γ production and lethality in lipopolysaccharide‐induced shock in mice , 1995, European journal of immunology.

[23]  G. Trinchieri,et al.  B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation , 1994, The Journal of experimental medicine.

[24]  P. Tipping,et al.  A role for P selectin in complement-independent neutrophil-mediated glomerular injury. , 1994, Kidney international.

[25]  P. Tipping,et al.  Evidence for delayed-type hypersensitivity mechanisms in glomerular crescent formation. , 1994, Kidney international.

[26]  J. D. Neely,et al.  Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. , 1994, Science.

[27]  G. Trinchieri,et al.  Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells , 1993, The Journal of experimental medicine.

[28]  Martin Bachmann,et al.  Disruption of the murine IL-4 gene blocks Th2 cytokine responses , 1993, Nature.

[29]  Soumitra Ghosh,et al.  Genetic analysis of autoimmune type 1 diabetes mellitus in mice , 1991, Nature.

[30]  P. Tipping,et al.  PARTICIPATION OF CELL-MEDIATED IMMUNITY IN DEPOSITION OF FIBRIN IN GLOMERULONEPHRITIS , 1988, The Lancet.

[31]  W. Couser,et al.  Crescentic glomerulonephritis without immune deposits: clinicopathologic features. , 1979, Kidney international.

[32]  L Adorini,et al.  The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. , 1998, Annual review of immunology.

[33]  P. Tipping,et al.  Interleukin-4 deficiency enhances Th1 responses and crescentic glomerulonephritis in mice. , 1998, Kidney international.

[34]  P. Tipping,et al.  Th1 responsiveness to nephritogenic antigens determines susceptibility to crescentic glomerulonephritis in mice. , 1997, Kidney international.

[35]  R. Wüthrich,et al.  Up-regulation of tubular epithelial interleukin-12 in autoimmune MRL-Fas(lpr) mice with renal injury. , 1997, Kidney international.

[36]  G. Trinchieri.  Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. , 1995, Annual review of immunology.

[37]  R. Locksley,et al.  The regulation of immunity to Leishmania major. , 1995, Annual review of immunology.