Natural autoantibodies against heat-shock proteins hsp70 and gp96: implications for immunotherapy using heat-shock proteins

Immunization of mice with cognate cancer-derived heat-shock protein (hsp) p reparations leads to protection from cancer growth. As hsp used for vaccina tion or therapy are derived from autologous cancers, questions of pathologi cal autoimmunity are of immense significance for the ongoing translation of this approach to therapy of human cancer. Employing the sera of normal adu lt mice as the first antibody, highly sensitive immunoblotting revealed the presence of anti-hsp natural autoantibodies in healthy animals. Natural au toantibodies of the immunoglobulin D (IgD) isotype bind to gp96, whereas hs p70 was recognized by IgD and IgM autoantibodies. Neither hsp was recognize d by the IgA, IgE or IgG immunoglobulins contained in the serum. The antige n-antibody recognition was titratable and dependent on the integrity of the IgD molecule. Sera from only a subset of the animals tested were found to be positive for autoantibodies against gp96 and hsp70, and individual and s train-specific variations were detected. Injection of gp96 into healthy mic e did not show sustained or consistent anti-gp96 IgD antibody response, cla ss switching, toxicity or pathological autoimmunity. IgD autoantibodies aga inst gp96 and hsp70 were also not detected in the autoimmune lpr mice. Thes e observations show the existence of a measured and tightly regulated natur al immune response to hsp.