Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease.
Injection of parental spleen cells into BDF1 mice results in a graft-vs-host disease (GVHD), the nature of which is critically dependent on the parental haplotype. B6-->BDF1 mice develop a Th1-mediated immunosuppressive lethal GVHD, whereas DBA/2-->BDF1 mice develop a Th2-dependent chronic GVHD, characterized by autoantibody production and glomerulonephritis. In this study we show that neutralizing endogenous IL-12 for a brief period during the initiation of acute GVHD in B6-->BDF1 mice not only confers long term protection from the acute disease, but also permits full repopulation of the recipient with donor B6 lymphocytes. Antibody-treated animals showed normal T cell proliferation in response to Con A stimulation and remained healthy throughout the study. Splenocytes from such mice showed reduced in vitro production of IFN-gamma and enhanced production of IL-5 and IL-10, suggesting a permanent switch from a Th1 to a Th2 cytokine response, comparable to that associated with chronic GVHD in DBA/2-->BDF1 mice. In contrast to DBA/2-->BDF1 mice, however, anti-IL-12-treated B6-->BDF1 mice displayed only mild B cell hyper-responsiveness, as evidenced by a modest increase in serum IgG and IgE levels and moderate levels of anti-dsDNA Abs. Importantly, however, anti-IL-12-treated B6-->BDF1 mice showed no evidence of immune complex-mediated glomerulonephritis. These results demonstrate that neutralizing IL-12 is an effective means of preventing acute GVHD and does not result in the development of chronic GVHD, which might otherwise limit its application.
Williamson
E
E
Department of Immunology, University of Glasgow, Scotland.
Garside
P
P
Bradley
J A
JA
More
I A
IA
Mowat
A M
AM
D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000009:adverse effects / Q000627:therapeutic use; D002678:Chimera / Q000276:immunology; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control*; D007136:Immunoglobulins / Q000097:blood; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology*; D007668:Kidney / Q000473:pathology; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016019:Survival Analysis; D018418:Th2 Cells / Q000276:immunology*
D000906:Antibodies; D016207:Cytokines; D007136:Immunoglobulins; D007519:Isoantigens; D018664:Interleukin-12