Biomedical subjects
Publications and source records attributed to E Gleichmann.
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The authors discuss the hypothesis that the spontaneously developing (angio-) immunoblastic lymphadenopathy of man as well as the various autoantibodies and constitutional symptoms accompanying this disease may be mediated by different reactions of T lymphocytes toward adjacent lymphocytes and macrophages, whose membranes were rendered incompatible by certain viruses or sensitizing drugs such as the antiepileptic compound diphenylhydantoin. This concept is based on two different lines of experimental evidence: (1) results obtained with animal graft-versus-host reactions, in which immunoblastic lymphadenopathy, angiogenesis, dermatitis and multiple autoantibody formation are known to be induced by reactions of parental T lymphocytes toward genetically foreign structures of the major histocompatibility complex; (2) experiments pointing to an essential similarity in T-cell reactions toward genetically foreign major histocompatibility structures on the one hand and self-major histocompatibility structures that were rendered "foreign" by viruses or chemicals on the other hand; (3) recent findings in mice that demonstrate a T-cell-dependent lymphoproliferation after the administration of diphenylhydantoin.
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It is proposed that the same diseases as those induced by the graft-versus-host reaction (GVHR) will arise in nonchimeric individuals, if structures of the major histocompatibility complex (MHC) on lymphocytes are altered, either by viral infection or by chemicals, in such a way that autologous T lymphocytes react against them as the react in the GVHR to semiallogeneic (F1) lymphocytes differing at the MHC. Diseases in which a GVHR-like pathogenesis is suspected will be discussed.
The aim of this study was to investigate malignant lymphomas of donor origin induced in F1 mice undergoing a chronic graft-versus-host reaction (GVHR) after injection of parental strain spleen cells. A total of 3 X 10(8) or 4 X 10(8) C57BL/10 spleen cells were administered to 7-8-week-old H-2 incompatible (C57BL/10 X HTG)F1 hybrids either as single or fractionated i.p. injections. Recipients were killed at intervals ranging from 1 month to 1 year after the first injection and their lymphoid cells typed for host-derived and donor-derived histocompatibility antigens. In 49% of the 88 GVH F1 mice, cells failed to be killed by a hyperimmune serum against HTG (H-2g) but reacted normally with antisera to C57BL/10 (H-2b) and, in the 9 cases tested, to theta-C3H. The conclusion that the lymphoid cells of these mice were derived from donor cells was supported by the finding that these animals lacked immunoglobulins bearing host-derived Iga allotype in their serum. Forty-three percent of the GVH F1 mice developed reticulum cell sarcomas (RCS), 32% revealed hyperplastic lymphoreticular tissue, and 25% showed no grossly abnormal changes. Mice with donor-type lymphoid tissues were found in all three groups; 50% of the 38 RCS detected were donor-type neoplasms. The induction of donor-type RCS during the GVHR strengthens the concept of lymphomagenesis through persistent stimulation with antigen(s).
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Primary lymphoid tumors were induced by inoculation of parental line spleen cells into H-2 incompatible F1 hybrid mice. The genotypes of lymphomas arising in 19 different parent yields F1 combinations were determined with cytotoxic antisera against H-2 specificities of donor and host. Additional chromosome marker studies established the reliability of tumor genotyping by the cytotoxicity test. According to H-2 typing, 12 primary lymphomas were of donor type, 66 of host type, and 14 of intermediate type. As a group, those parent yields F1 combinations in which donor-type lymphomas developed (group 1) showed a higher degree of histocompatibility between donor and host than those combinations in which donor-type lymphomas failed to appear (group 2). Allogeneic inhibition may have suppressed the development of donor-type tumors in the combinations of group 2. The development of malignant lymphomas of donor-type in the graft-versus-host reaction (GNHR) supports the concept of lymphomagenesis as a consequence of persistent stimulation by antigen.
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The pathogenesis of glomerulonephritis in F(1) hybrid mice injected with parental spleen cells was investigated in several ways. Whenever glomerulonephritis developed, the lesion had the typical morphology produced by antigen-antibody complexes. Experiments employing backcross mice demonstrated that the antigen is supplied by the recipient and that it is specified by the H-2 gene complex, or by a locus closely linked to H-2. The source of the antibody was investigated by staining glomerular lesions with fluorescein isothiocyanate-tagged anti-immunoglobulin allotype sera. Only donor-type allotypes could be detected. The ability of the donor's immunocytes to respond to the recipient's histocompatibility antigens in such a way as to produce nephritogenic immune complexes varied from strain to strain, and seemed to be controlled by a gene unrelated to H-2. The results suggest that cell surface antigens, such as histocompatibility antigens, may be of importance in the pathogenesis of several kinds of glomerulonephritis.
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