The lymphokine, soluble immune response suppressor (SIRS), is a product of interferon or mitogen activated human or murine suppressor T lymphocytes which is activated to SIRS-ox by H2O2 or by macrophages. Catalase and the immunopharmacological agent levamisole inhibit activation of SIRS to SIRSox and various electron donors inactivate SIRS-ox. SIRS-ox inhibits immune responses in vivo and in vitro and inhibits division by tumor cell lines. Inhibition of tumor cell division appears to be caused by SIRS-ox-mediated oxidation of cellular protein sulfhydryls. Two intracellular processes inhibited by SIRS-ox are microtubule function and DNA replication. Additionally, growth factors interfere with the immunosuppressive properties of SIRS/SIRS-ox. Since most biological processes are tightly controlled by both positive and negative regulation, these observations suggest that SIRS/SIRS-ox may represent an important negative regulator of cell proliferation. Depressed immunity has been documented in a variety of diseases and in nephrotic syndrome is associated with increased levels of SIRS excreted in urine. Interferon, an important regulatory protein, is hoped to have therapeutic potential in the treatment of various viral or neoplastic diseases. Lack of progress in this area may not relate to the purity, amount or type of interferon administered but may instead relate to the type of regulatory cells interferon interacts with, such as suppressor T cells. The immunopharmacological agent, levamisole, has been used to restore immunity in diseases associated with depressed immunity and inhibits activation of SIRS to SIRS-ox. Taken together, these observation suggest that SIRS/SIRS-ox may be important in various diseases associated with depressed immunity. The purpose of this proposal is to: 1) define the apparent oxidative basis of SIRS-ox activity; 2) determine the mechanism by which SIRS-ox inhibits microtubule assembly and DNA replication; 3) continue to explore the biology of SIRS/SIRS-ox; 4) purify human SIRS and compare and contrast it to murine SIRS; and 5) begin to assess the biological and pathological role(s) of SIRS/SIRS-ox in various in vitro and in vivo models.
| Schnaper, H W; Aune, T M (1987) Steroid-sensitive mechanism of soluble immune response suppressor production in steroid-responsive nephrotic syndrome. J Clin Invest 79:257-64 |
| Schnaper, H W; Aune, T M (1986) Suppression of immune responses to sheep erythrocytes by the lymphokine soluble immune response suppressor (SIRS) in vivo. J Immunol 137:863-7 |
