Carl W. Pierce

Inhibition of interleukin 1 (IL-1)-elicited leukocytosis and LPS-induced fever by soluble immune response suppresor (SIRS)

IL-1-induced leukocytosis was inhibited or blocked in a dose-dependent manner by SIRS, an antigen-nonspecific suppressive lymphokine, when administered intravenously or per os to CBA mice. Timing experiments showed that SIRS effectively inhibited the leukocytosis when administered within 30 minutes of the IL-1. An antipyrogenic activity of SIRS was observed in rabbits injected intravenously with LPS. SIRS, given intravenously in one or two doses, markedly reduced LPS-induced fever. SIRS (2000 units) was a more effective antipyretic agent than aspirin (3 mg/kg body weight, intramuscularly). The results suggest that SIRS may be a potential drug for use in IL-1-mediated disorders.

Characterization of an Antigen-Specific Suppressor Factor Generated by Cell-Free Translation

Recent advances in hybridoma technology and biochemical methodology have enabled a more quantitative analysis of antigen-specific suppressor T-cell products. Using reverse phase and high performance liquid chromatography (HPLC), it has been possible to purify to apparent chemical homogeneity several of these suppressor factors, TsF, specific for the antigen, GAT (1,2). Although the availability of such purified material allows dissection of the TsF protein at the biochemical, serological and potentially functional levels, it does not permit any detailed analysis of the events involved in factor production or the molecular organization of factors at the DNA level.

Characterization of GAT-Specific Suppressor Factors and Comparison to Other Antigen-Specific Factors

The discovery that thymus-derived lymphocytes (T cells) were essential for antibody responses but the precursors of the antibody producing cells came from bone marrow lymphocytes (B cells) gave birth to cellular immunology. These observations led to the hypothesis that lymphocytes are composed of functionally distinct subsets of interacting cells. This paradigm was used subsequently to interpret the data that not all T cells were helper T cells. Thus, T cells are now regarded as a heterogeneous collection of cells consisting of regulatory and effector cells. Cytotoxic T cells and cells that mediate delayed hypersensitivity responses are classed as effector T cells. Regulatory T cells that collaborate with B cells and effector T cells are referred to as helper T (Th) cells, whereas those that inhibit responses of other lymphocytes are called suppressor T (Ts) cells. The concerted activities of helper and suppressor T cells provide a highly sophisticated system to finely tune immune responses.

Antigen-Specific Suppressor T Cells as One Mode of Expression of Immune Response Genes

Two models to explain the cellular site and mechanism of expression of MHC linked immune response (Ir) genes are currently popular. One model holds that the immune response gene is expressed as a defect in the T cell receptor repertoire such that T cells from nonresponder animals are unable to recognize antigens under Ir gene control in the context of self MHC antigens and, thus, are not stimulated. However, the same antigen may be recognized in the context of allo-MHC components under conditions where alloreactivity has been abolished. Ample experimental evidence exists in the literature to support this model (1–4). The alternative model to explain Ir gene function, the determinant selection hypothesis, centers around the concept that antigen presenting cells from nonresponder animals fail to display foreign antigenic determinants in the proper array with self MHC determinants. Again, ample experimental evidence is available to support this model (5–8).

Identification of H-2-Restricted Suppressor T Cell Factors Specific for L-Glutamic Acid50-L-Tyrosine50(GT) and L-Glutamic Acid60-L-Alanine30-L-Tyrosine10(GAT)

The synthetic polymers GAT and GT are closely related antigens that stimulate responses regulated by genes in the I region of the H-2 gene complex. The responses stimulated by these two antigens are distinct and the genetics of the regulation of the immune responses are different. First, some mice (H-2a,b,d,k) produce antibody and develop T cell proliferative responses to GAT while others (H-2p,q,s) do not (1–4); whereas, none of the inbred strains of mice tested produce antibody or develop proliferative responses to GT (5,6). All mice produce specific antibody and are primed for T cell proliferative responses to GAT or GT when immunized with GAT or GT complexed to methylated bovine serum albumin (MBSA). Second, GAT stimulates specific suppressor T cells in all non-responder strains (7,8), whereas GT stimulates suppression in some (H-2k,d,s), but not other (H-2a,b,q) nonresponder mice (9,10). Production of GAT specific suppressor T cells is not limited to nonresponder strains of mice, since similar T cells have been detected in adult responder strains of mice that were injected intravenously with GAT or GAT-pulsed macrophages (GAT-Mo) as neonates (11).

L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT): A probe for regulatory mechanisms in antibody responses.

The synthetic random terpolymer of L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) has been used as a probe to investigate regulatory mechanisms in antibody responses in tissue culture systems. In this brief review, the mechanisms of H-2 linked Ir gene control of antibody responses to GAT and genetic restrictions governing Mphi-immune T cell interactions in antibody responses to GAT are summarized.