Biomedical subjects
Publications and source records attributed to D B Amos.
Data illustrating the inheritance of a Gm1,2,17,5,13,14 haplotype in a Caucasian family are presented. The mother and two children are heterozygous for this unusual haplotype. The possible origin of the haplotype is discussed.
Asymmetry in the relationship between the H-2K mutant strain C57Bl/6.CH-2ba (H-2ba) and the wild-type congenic C57Bl/6 has been demonstrated both in MLR and serologically by haemagglutination. MLR between these strains, when B6 was the responder, was as strong as that toward allogeneic stimulator cells: H-2ba was regularly less responsive toward B6. Responses in both directions were increased, in terms of augmented proliferative responses, by prior immunization. In this context the MLR resembles that towards minor H-locus antigens rather than those controlled by the H-2 locus. Immunization of (H-2ba X BALB/c)F1 hybridgs with B6 lymphoid cells induced the production of a haemagglutinating antibody not directed toward any known H-2 specificity. The B6 haemagglutinogen, termed He, was present on B6 lymphoid as well as red blood cells. Segregation studies of F2 and back-cross progeny of (H-2ba X BALB/c)F1 hybrids suggest that the response to He is controlled by two Ir genes, one of which is linked to H-2.
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Exposure to supralethal total body irradiation and transplantation of bone marrow from a DLA- and pedigree-identical donor have regularly produced successful engraftment and the establishment of stable long-term chimerism in beagles of the Cooperstown colony. Bone marrow allografts performed in pairs of dogs bearing identical DLA haplotypes derived from different pedigree origins (i.e., different classes of the same haplotype) yielded two different results. Depending upon the particular haplotype pedigree combination used, such transplants either led to long-term chimerism or to failures of engraftment, secondary disease, and death of the recipients (i.e., pedigree-incompatible combinations). Radiation chimeras given bone marrow from a DLA-and pedigree-identical donor were challenged within 8-12 h after marrow transplantation with a renal allograft obtained from another DLA- and pedigree-identical donor. The recipients have remained unresponsive to such renal allografts and have survived indefinitely with normal renal function. In contrast, renal allografts obtained from donors bearing the same DLA haplotypes derived from pedigree-incompatible sources were rejected within 25-50 days after transplantation. The long-term surviving recipients have also been unresponsive to skin allografts obtained from their donor of marrow and the kidney donor. Skin grafts obtained from other DLA- and pedigree-identical dogs were rejected within 13-41 days, and grafts from DLA-incompatible donors survived for 10-25 days. These results highlight the potential importance of genetically controlled histocompatibility determinants other than DLA in conditioning allograft reactivity. The determinants uncovered in the present study appear to be linked to the DLA complex, as demonstrated by the ability of the pedigree origins of DLA haplotypes present in individual dogs to serve as an effective marker system for such non-DLA antigen(s). The results also point to the potential usefulness of the early postirradiation period for the induction of allogeneic unresponsiveness in large adult mammals.
The effects on some host defenses of murine cytomegalovirus (MCMV) and(or) EL(4), a mouse ascites homograft, were studied in mice. Assays of cellular and humoral immunity in response to either or both of these perturbations were carried out by quantitation of various immune activities.Limited studies demonstrated no effect of EL(4) inoculation on the host response to MCMV by organ viral titer, duration of viral persistence, or anti MCMV complement-fixing antibody titer. Prior infection with MCMV, however, resulted in greatly reduced numbers of splenocytes, the source in this study of immune effector cells. Residual splenocytes demonstrated less response to both phyto-hemagglutinin and lipopolysaccharide, particularly in the 2-3-wk interval after infection. Similarly, responder cells in mixed lymphocyte cultures were less reactive when derived from infected animals. Lymphocyte-mediated cytolysis of EL(4) was significantly less in mice infected on the day of and 7, 14, and 21 days before the tumor homograft with a return to control levels by 28 days. 90% of the cell-mediated cytolysis could be eliminated by treatment with anti-theta serum. Serum-mediated cytolysis of EL(4) was also reduced in infected animals. No suppressor cells or serum inhibitory factors could be identified in infected animals. Although alternative explanations exist, this study suggests that in infected animals there is a significant reduction in both the number and function of bone marrow-derived and thymus-derived cells directed against the alloantigens in EL(4).
H-2 antigens from EL4 (H-2b) and RLmale 1 (H-2d) leukemias were solubilized with deoxycholate and partially purified based on their adherence to a Lens culinaris hemagglutinin column. In double reciprocal experiments we have shown that these preparations specifically inhibit conjugate formation between target cells and alloimmune peritoneal lymphocytes, a preparation rich in cytotoxic T lymphocytes.
Natural killing (NK) capacity was evaluated in peripheral blood mononuclear cells from 14 patients with well defined primary immunodeficiency disorders and compared with the activity of those cells in antibody-dependent cell-mediated cytotoxicity (ADCC) assays against antibody-coated erythrocyte (killed primarily by monocytes) and lymphoid or tumor targets (killed exclusively by lymphoid cells). A selective inability to lyse antibody-coated lymphocyte targets was observed with cells from patients with x-linked agammaglobulinemia, suggesting the involvement of either a different lymphocyte subpopulation or membrane receptor for NK and ADCC, or that a different functional susceptibility exists for the two types of killing. The only immunodeficiency state in which lymphocyte NK activity was found to be lacking was severe combined immunodediciency disease.
The evolution of HLA specificities has been toward ever-increasing refinement; one example is a subdivision of HLA-B5, the supertype specificity originally defined as 4a. HLA-B5 can now be further subdivided into Bw51 amd Bw52 by serologic means. Whereas the specificity Bw51 can be detected by specific sera, the identification of Bw52 must frequently be deduced from knowledge of B5 and Bw51, although serology has progressed rapidly. There has been no comparable development in identifying fine specificities by cellular cytotoxicity in populations. We have now found that cytotoxic effectors of exquisite specificity can be generated against Bw52 by sensitization of cells from a Bw51 donor and vice versa; Bw51 and Bw52 can in this way be recognized with equal ease. This may set a precedent for recognizing fine specificities of other HLA antigens that cannot yet be identified serologically or can be identified only imprecisely. These fine distinctions may have great relevance in allotransplantation and in understanding disease susceptibility.
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Seventy B-cell alloantisera were tested by microcytotoxicity against a panel of B-cell-enriched and T-cell-enriched lymphocytes. Six groups were discerned and have tentatively been designated DIg 1-7 (for Duke immunoglobulin-positive cell groups). These alloantisera were used to type an HLA-A/B recombinant family. Two groups were observed to segregate in this family, DIg 7 with the HLA-B locus and DIg 2 with the HLA-A locus.
Serum antibodies to adenovirus (ADN), cytomegalovirus (CMV), herpes simplex virus (HSV), influenza (INF), para-influenza (PAR), mumps (MUM), coxsackie B4 (Cox B4) and B5 (Cox B5) viruses were measured from 584 individuals belonging to 21 Indiana Amish families. Sex and age effects on antibody responses to cytomegalovirus were observed. Age effect on CMV, HSV, INF, PAR, MUM responses were also found. The percentage of responders to some of the viruses was shown to be age dependent, but the levels of antibody response were not affected by the difference in age. A familial basis for the antibody response was demonstrated. Attempts at demonstrating association between HLA haplotypes and responses were not successful. The unlikelihood of predominantly HLA-associated control of viral antibody response was discussed.
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