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Biomedical subjects

E M Shevach

Publications and source records attributed to E M Shevach.

At least 235 records · Page 13Linked to original sources
PubMed1976

Mutant lines of guinea pig L2C leukemia. I. Deletion of Ia alloantigens is associated with a loss in immunogenicity of tumor-associated transplantation antigens.

Five different lines of a strain 2 guinea pig leukemia (L2C) which had been carried in different laboratories share certain chromosomal markers and have a common surface immunoglobulin idiotypic determinant indicating that they have a common origin. All these leukemic lines have on their surface of the B alloantigen (equivalent of the murine H-2K and H-2D antigens) and four of these five lines have on their surface the Ia alloantigens normally present on the strain 2 lymphocytes. The result of a study of the growth and rejection patterns of these leukemias in inbred and random-bred guinea pigs of selected histocompatibility type indicates that both the B and Ia antigens can act as transplantation antigens in guinea pigs. Immunization protection tests in syngeneic animals demonstrated that the four Ia-positive leukemias possessed a tumor-associated transplantation antigen (TATA), while the one Ia-positive leukemias possessed a tumor-associated transplantation antigen (TATA), while the one Ia-negative leukemia by this criteria did not appear to have TATA. However, crisscross immunization protection tests demonstrated that preimmunization of syngeneic animals with an Ia-positive L2C line lead to a subsequent protection against challenge with the Ia-negative leukemia. Immunization with the Ia-negative line never protected against a subsequent challenge with any of the leukemic cells of L2C lines. These results strongly suggest that the Ia-negative leukemia possessed a TATA that can be recognized but is not itself immunogenic, and also indicate that Ia antigens on L2C cells are functionally associated with TATA and can act as immunological carries for tumor transplantation determinants.

Animals↗
PubMed1976

Structural characteristics of the alloantigens determined by the major histocompatibility complex of the guinea pig.

The GPLA B and Ia (I region-associated) antigens are the products of genes found in the guinea pig major histocompatibility complex. Because of their importance in immune response phenomena, a structural study of these antigens was undertaken. [3H]leucine and [3H]fucose were internally incorporated into guinea pig lymph node cells. The GPLA B and Ia antigens were solubilized by the nonionic detergent Nonidet P-40, purified by affinity chromatography using an adsorbent column of lentil lectin, isolated by immunoprecipitation, and examined by discontinuous polyacrylamide-sodium dodecyl sulfate gel electrophoresis. The GPLA antigens B.1, B.2, B.3, and B.4, were shown to be glycoproteins of mol wt 40,000 daltons and to be noncovalently associated with a 12,000 dalton protein. The molecules bearing B.2 and B.3 in a B.2/B.3 heterozygote are shown to be separable, suggesting the antigenic determinant is a primary gene product. In addition, a new GPLA determinant, S, which resembles the B antigen in that it is found on a molecule of approximately 40,000 daltons, was studied. In a B.2/B.3 S+ animal the molecule bearing antigen S was shown to be independent of those bearing B.2 and B.3, providing evidence that the genes determining B and S are at separate loci. The Ia-bearing molecules identified by anti-Ia.2,4 are glycoproteins of mol wt 58,000 daltons which are composed of two subunits of 33,000 and 25,000 daltons, respectively, linked by disulfide bonds. The Ia-bearing molecules are independent of GPLA-bearing molecules, indicating different loci determining these antigens. By all criteria, the guinea pig GPLA B antigens appear homologous to the murine H-2D and H-2K antigens, while the guinea pig Ia antigens appear homologous to the Ia antigens of the mouse.

ABO Blood-Group System↗
PubMed1976

The function of macrophages in antigen recognition by guinea pig T lymphocytes. III. Genetic analysis of the antigens mediating macrophage-T lymphocyte interaction.

Activation of immune T lymphocytes by antigen-pulsed macrophages is mediated by the Ia antigens of the guinea pig MHC or the products of closely linked genes. Studies using combinations of macrophages and T cells derived from outbred animals with different Ia antigens and/or Ir gene products have demonstrated that sharing of Ir gene products between macrophage and T cells is not sufficient for effective macrophage-T cell interaction. The role of the Ia antigens in the absence of the linked Ir gene products could not be directly examined because we were unable to identify an animal which bore the full complement of Ia antigens in the absence of the Ir gene that is normally associated with them. The results of these studies support the concept of the functional expression of the Ir gene product in the macrophage.

Animals↗
PubMed1976

The role of the macrophage in genetic control of the immune response.

The ability of an animal to mount an immune response is controlled by a number of autosomal dominant immune response (Ir) genes that are linked to the major histocompatibility complex of the species. In the guinea pig, alloantiserums raised by cross-immunization of inbred strain 2 and strain 13 animals specifically inhibited the in vitro proliferative responses of (2 X 13) F1 lymphocytes to those antigens the response to which is controlled by Ir genes linked to the alloantigens against which the serums are directed. A genetic analysis indicated that the inhibitory activity of the alloantiserums was directed against the alloantigens rather than the products of specific Ir genes. The interaction of antigen-pulsed macrophages with immune T lymphocytes is also mediated by the 2/13 alloantigens and alloantiserums are capable of inhibiting macrophage-T lymphocyte interaction. Studies involving combinations of macrophages and lymphocytes that differed at alloantigens or Ir gene products or both raised the possibility of the expression of the Ir gene product in the macrophage.

Animals↗
PubMed1976

Macrophage-lymphocyte interaction. III. Site of alloantiserum inhibition of T lymphocyte proliferation induced by allogeneic or aldehyde-bearing cells.

Inhibition by anti-Ia sera of guinea pig T lymphocyte proliferation induced by allogeneic macrophages (MLR) and NaIO4 or neuraminidase-galactose oxidase-treated macrophages has been investigated in order to identify the target cell upon which the antisera act. Anti-2 and anti-13 alloantisera were found to inhibit both MLR and aldehydeinduced T cell reactivity when directed against the specificity of the stimulatory macrophage. Little or no inhibition was observed when these antisera were directed against the T lymphocyte specificity when cultures were harvested at the time of peak proliferation. In addition, anti-2 serum was found to inhibit macrophage-lymphocyte rosett formation at 20 hr between neuraminidase-galactose oxidase-treated strain 2 macrophages and strain 13 lymphocytes. These findings demonstrate that inhibition of T cell proliferation can be produced by anti-Ia sera directed against the macrophage and raise the possibility that Ir gene products may function in part at the level of the macrophage.

Animals↗
PubMed1976

Mutant lines of guinea pig L2C leukemia. III. The reaction of an alloantiserum detecting idiotypic determinants on a clonally derived guinea pig B cell leukemia with IgM and Ia molecules.

An alloantiserum was prepared in a strain 13 guinea pig against the GH line of the strain 2 guinea pig L2C leukemia. This serum contained antibodies to both IgM and Ia molecules. After absorption with normal spleen cells from a strain 2 guinea pig, this antiserum no longer reacted with strain 2 cells, but detected idiotypes on the IgM molecules of the L2C leukemia. These idiotypes were on the same IgM molecules detected by a xenogeneic sheep anti-L2C Fab mu antiserum. As assayed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the idiotype-bearing IgM molecules were synthesized by the cell, composed of normal sized mu and light chains, appeared on the cell surface as monomeric IgM, and were the only immunoglobulin molecules present on the cell. Although the alloantiserum potentially contained antibodies to unique Ia idiotypic determinants, none were found. Furthermore, the anti-IgM idiotype antisera did not react with any Ia-like molecules.

Animals↗
PubMed1975

In vitro selection and extended culture of antigen-specific T lymphocytes. I. Description of selection culture procedure and initial characterization of selected cells.

Specific selection of antigen-responsive guinea pig peritoneal exudate lymphocytes (PELs) was achieved by a selection culture procedure. This procedure involved the addition of PELs from immune donors to monolayers of antigen-pulsed adherent peritoneal exudate cells from nonprimed syngeneic donors. PELs which failed to adhere were discarded at 24 and 48 h; after 1 wk of culture, lymphocytes were obtained which were highly responsive to the antigen for which they were selected but which demonstrated little or no response to other antigens to which the original donor of the lymphocyte was immune. These selected cells were largely T lymphocytes and could be maintained in culture for 2-5 wk in an antigen-responsive state and, in 20-30% of cases, for 8-10 wk in an antigen-independent state.

Albumins↗
PubMed1975

Guinea pig immune response-related histocompatibility antigens. Partial characterization and distribution.

We have previously demonstrated that guinea pig alloantisera directed at strain 2 and strain 13 membrane antigens block specific lymphocyte activation in immune response gene-controlled systems. In this communication we describe the partial characterization of the antigens against which these antisera are directed (the 2 and 13 antigens) and, in addition, that of the B antigen which by distribution resembles the human HL-A and mouse H-2 major histocompatibility antigens. Lymphoid cells from strain 2 and strain 13 guinea pigs were surface labeled with 125I by the lactoperoxidase technique. Nonidet P-40 extracts of these labeled cells were precipitated by sandwiches of strain 2 antistrain 13, strain 13 antistrain 2, or outbred anti-B antisera, followed by rabbit antiguinea pig immunoglobulin antisera. Precipitates were dissolved in sodium dodecyl sulfate (SDS) and electrophoresed on SDS polyacrylamide gels. Radioactive peaks representing the 2 and B-cell membrane antigens were obtained from strain 2 lymph node cells, as well as from a B-lymphoid cell population (L2C leukemia cells) and a T-lymphocyte population (STRAIN 2 PERITONEAL EXUDATE LYMPHOCYTES [PELs]). Radioactive peaks representing the 13 and B-cell membrane antigens were obtained from strain 13 lymph node cells and strain 13 PELs. All anti-B precipitates produced two peaks when electrophoresed on SDS polyacrylamide gels; one representing an antigen with a mol wt of approximately 45,000, and one representing an antigen with a mol wt of about 12,000. Both may be components of a single protein. All anti-2 and anti-13 precipitates produced a single peak when electrophoresed on SDS polyacrylamide gels. Both the 2 and 13 antigens were found by this technique to have mol wt of approximately 25,000. By molecular weight criteria, as well as by previously investigated distributional criteria, the B antigen is similar to the human LA and Four antigens, and to the mouse D and K antigens, and the 2 and 13 antigens are similar to the mouse Ia antigens.

Animals↗
PubMed1975

Membrane receptor sites for the identification of lymphoreticular cells in benign and malignant conditions.

The cells of the lymphoreticular system are heterogeneous both morphologically and functionally. The bone marrow derived (B) lymphocyte can be identified by the presence of easily detectable surface immunoglobulin and a receptor for antigen-antibody-complement (EAC) complexes. Monocytes and histiocytes also bear a receptor for EAC and in addition possess a receptor for cytophilic antibody detected with red cell--IgG complexes (IgGEA). In man, thymus derived (T) lymphocytes form non-immune rosettes with sheep red blood cells (E). We have examined a number of malignant lymphoreticular populations for the presence of the EAC, EA, and E receptors on suspensions of cells and have adapted the technique to demonstrate the EAC and EA receptors on frozen tissue sections. Rosetted malignant cells can also be cytologically examined on Millipore filters. The malignant cells both in section and suspension from the spleens and lymph nodes of 6 patients with nodular lymphoma bound EAC but not IgGEA or E; by these criteria these malignant cells are of B lymphocytic origin. The malignant cells from the spleens of 2 patients with leukaemic reticuloendotheliosis and 1 patient with malignant histiocytosis could be classified as being of histiocytic origin by the selective binding of IgGEA. In 3 cases of diffuse lymphocytic lymphoma the malignant cells bound only E and are therefore of T lymphocytic origin. The application of these techniques to the classification of malignant lymphoma may lead to important theoretical and therapeutic advances.

Animals↗
PubMed1975

Macrophage-lymphocyte interaction and antigen recognition.

The functional and morphologic aspects of immunologically relevant macrophage-lymphocyte interaction have been characterized in inbred guinea pigs. Antigen-dependent initiation of in vitro DNA synthesis in lymphocytes taken from animals previously immunized with that antigen has been shown to be macrophage dependent. Expression of this in vitro correlate of in vivo established cellular immunity requires that antigen is initially bound to macrophages antecedent to any interaction with the specific lymphocyte. In view of the failure of supernatants from macrophages briefly exposed to antigen to initiate DNA synthesis in immune lymphocytes and the critical density requirements for lymphocyte proliferation, it is reasonable to assume that a direct physical interaction occurs between the antigen-bearing macrophage and lymphocyte. Using an in vitro assay of lymphocyte binding to macrophage monolayers, we have characterized what appear to be sequential events in macrophage-lymphocyte interaction. The initial event is an antigen-independent interaction between macrophage and lymphocyte whose characteristics are rapid reversibility, species but not strain specificity, and dependence on macrophage metabolism. If macrophages bear antigen for which a given lymphocyte possesses a specific receptor, then a second nonreversible antigen-dependent stabilization of binding occurs. This latter step requires tht macrophage and lymphocyte be histocompatible. These observations parallel functional studies of the histocompatibility dependence of macrophage-associated antigen initiation of lymphocyte DNA synthesis in guinea pigs. A model sequence of the physical events correlating with functional macrophage-lymphocyte interaction is proposed.

Animals↗
PubMed1975

Antigenicity of carcinogen and viral induced sarcomas in inbred and random bred guinea pigs.

A tumor specific transplantation antigen (TSTA) has been detected in a methylcholanthrene (MCA) induced guinea pig tumor. It was possible to induce resistance to rechallenge with the tumor by immunization with irradiated cells in CFA. In contrast, the same technique failed to detect TSTA in two viral (Kirsten strain mouse sarcoma virus, Ki-MSV) induced guinea pig tumors; these results are similar to observations made with mouse Ki-MSV-induced tumors. Transplantation studies with these tumors in both inbred and random-bred guinea pigs showed a complexity of growth and rejection patterns. The B alloantigen, a major serologically defined antigen of the guinea pig histocompatibility complex, seemed to play a central role in acting as a guniea pig transplantation antigen. In all cases studied, the absence of B antigens in the recipient led to tumor rejection and anti-B antibody protection.

Animals↗
PubMed1975

The effect of alloantisera on antigen-induced T cell proliferation.

In the guinea pig, alloantisera raised by cross-immunization of strain 2 and strain 13 animals are capable of specifically inhibiting the in vitro proliferative response of (2 X 13)F1 T lymphocytes to those antigens the response to which is controlled by Ir genes linked to the genes controlling the alloantigens against which the serum is directed. However, in similar studies performed in the two parental strains, the responses to antigens not known to be under unigenic control were also markedly inhibited by the appropriate alloantisera. We have extended our studies of this "nonspecific" inhibitory effect of alloantisera on T cell proliferation and have demonstrated that the proliferative response of strain 2 and strain 13 T cells to a large number of antigens is markedly inhibited by anti-2 and anti-13 sera, respectively. Antisera to the B alloantigen, the product of a linked but distinct histocompatibility locus, which is present in both strain 2 and strain 13 animals, also produced a marked inhibition of T-lymphocyte proliferation. A number of possible explanations for the generalized inhibitory effect of alloantisera on T cell proliferation are discussed.

Animals↗
PubMed1975

The major histocompatibility complex of the guinea pig. I. Serologic and genetic studies.

Serologic and genetic studies of the antigens which comprise the guinea pig MHC have demonstrated three distinct but linked genetic regions. Antisera to the B region were raised by cross-immunization of random-bred animals; this region controls antigens B.1, B.2, B.3, and B.4 which behave as alleles at a single locus and which resemble the products of the murine D or K region genes in their tissue distribution and molecular characteristics. Cross-immunization of inbred strain 2 and strain 13 animals, both of which bear the B.1 antigen, leads to sera which identify antigens which resemble the products of the I region of the murine MHC. Specific absorption experiments have demonstrated four distinct I region antigens. In addition to the B and I regions, inbred strain 2, strain 13, and some outbred animals bear an antigen (S.1) which is the product of a third genetic region and which also resembles the murine D or K region gene products in molecular size. The results of these studies should facilitate the use of the guinea pig as an experimental model for studies of genetic control of the immune response and the function of the histocompatibility-linked Ir genes.

Animals↗