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 capacity in T or B cells demonstrate profound immune dysregulation, as evidenced by increased lymph node size, expression of markers of memory activation on T cells, inflammation in a variety of tissues and development of autoantibodies. However, 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, the present studies were designed to determine if administration of 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 as 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 the functional status of the immune system. Mice were injected with 1 mg mouse (approximately 50 mg kg) of 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) cell 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 recoveries, increased percentages of macrophages, decreased percentages of NK cells, decreased phagocytic activity, decreased proliferative responses to mitogens and slight increases in T and B cells displaying an activated phenotype. Many of these same parameters examined in the lymph nodes were not altered by the anti-TGF-β treatment. The thymus was decreased in size, but altered only slightly in one population of developing T cells. Most of the changes observed were modest and returned to control levels after discontinuation of treatments. The only serological finding was an increase in IgA levels in anti-TGF-β-treated mice, but