Increased IL-6 production and IL-6-mediated Ig secretion in murine host-vs-graft disease.
BALB/c mice neonatally injected with semiallogenic (A/J x BALB/c)F1 splenocytes develop a host-vs-graft (HVG) reaction between host T cells and donor B cells, resulting in hypergammaglobulinemia, splenomegaly, and increased serum levels of various autoantibodies. This syndrome is associated with a polyclonal activation of the donor-derived B cells. High serum levels of IL-6 were found in 4-wk-old mice undergoing HVG disease (mean +/- SEM, 132 +/- 93 as compared with 12 +/- 2 in control mice, p < 0.05). Also supernatants of spleen cell cultures from HVG mice contained increased levels of IL-6. In situ hybridization and cell depletion experiments demonstrated that host macrophages were responsible for this pathologic IL-6 secretion. The spontaneous in vitro production of autoreactive antibodies by donor B cells from HVG mice was further enhanced by adding human rIL-6, whereas addition of human rIL-1 beta, human rIL-2, murine rIL-4, murine rIL-5, or combinations of these cytokines had no effect. Finally, addition of blocking anti-IL-6 and anti-IL-6 receptor mAb markedly reduced hyper IgG1 production in cultures of spleen cells from HVG mice. These data suggest that an increased production of IL-6 by persistently stimulated host macrophages is involved in the activation of donor B cells leading to HVG disease.
Vandenabeele
P
P
Laboratorium voor Moleculaire Biologie, Universiteit, Gent, Belgium.
Abramowicz
D
D
Berus
D
D
Van der Heyden
J
J
Grooten
J
J
Donckier
V
V
Hooghe-Peters
E L
EL
Goldman
M
M
Fiers
W
W
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007136:Immunoglobulins / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000502:physiology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C
D007074:Immunoglobulin G; D007136:Immunoglobulins; D015850:Interleukin-6