Minimal Effects on Immune Parameters Following Chronic Anti-TGF-β Monoclonal Antibody Administration to Normal Mice.

Mice genetically deficient in TGF-β1 or TGF-β signaling c apacity in T or B cells demonstrate profound immune dysregulation, as evidenced by increased lymph node size, expression of markers o f memory/activation on T cells, inflammation in a variety of tissues and development of autoantibodies. H owever, this constant and complete lack of TGF-β1 or TGF-βR signaling may not reflect effects of TGF-β neutralization using antibodies in mature animals. Thus, t he present studies were designed to determine if administration o f an anti-TGF-β monoclonal antibody (neutralizes TGF-β1, 2 and 3) to mature, normal mice results in evidence of immune dysregulation or immune-mediated pathology. An initial study examined daily administration of 0.25, 0 .75 and 2.5 mg/kg of anti-TGF-β to mice for three weeks, achieving blood levels of as high a s 9 mg/ml. Comprehensive hematological and histopathological evaluation showed no evidence of pathology. A second study was designed to extend the antibody treatment period and further examine t he functional status of the immune system. Mice were injected with 1 mg/mouse ( approximately 5 0 m g/kg) o f anti-TGF-β (1D11) three times per week achieving circulating blood levels of 1-2 mg/ml. Many parameters of immune status were assessed, including natural killer ( NK) c ell activity, lymphocyte proliferative responses, phagocytic activity, phenotypic assessment of leukocyte subsets, and serum measurements of proinflammatory cytokines, autoantibodies and immunoglobulin isotypes. In addition, histopathological assessment of heart, lungs, liver, kidney, salivary glands, skin, spleen and lymph nodes was also performed. Very few of the multiple immune parameters examined showed detectable changes in anti-TGF-β-treated mice. Changes that were observed were primarily restricted to the spleen and included increased spleen cell r ecoveries, increased percentages of macrophages, decreased... [ABSTRACT FROM AUTHOR]