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R Melvold

Publications and source records attributed to R Melvold.

11 recordsLinked to original sources
PubMed1995

Mutation of a major histocompatibility class I locus, H-2D, leads to an increased virus burden and disease susceptibility in Theiler's virus-induced demyelinating disease.

Genetic studies have demonstrated that susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease is multigenic with linkage to the MHC class I locus, H-2D. We have analyzed the effect of mutations (H-2bm13 and H-2bm14) in the H-2Db gene on central nervous system (CNS) virus replication, virus-specific delayed type hypersensitivity (DTH) and disease induction in mutant [bm14D2F1 and bm13D2F1] and parental B6D2F1 hybrids. The results indicate that substitutions of only a single residue (bm14D2F1) or three residues (bm13D2F1) in H-2D in the mutant leads to a sequence of events culminating in disease susceptibility. Mutation of the H-2D gene is associated with reduced or delayed virus clearance following the acute phase of exponential CNS virus growth and an increased level of virus persistence. Concomittant with the greater virus antigen burden, mutant mice respond with higher levels of virus-specific DTH and develop inflammatory demyelinating lesions.

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PubMed1993

Effects of irradiation on development of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in genetically resistant mice.

Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a model for multiple sclerosis, is a chronic T cell-mediated disease. Development of clinical symptoms in susceptible mouse strains generally correlates with TMEV-specific delayed-type hypersensitivity (DTH) responses. These responses, minimal or absent in resistant mouse strains, have been proposed as the pathogenic basis for the central nervous system inflammation and demyelination characterizing the disease. We demonstrate here that normally resistant (C57BL/6 x DBA/2)F1 hybrid mice develop clinical symptoms and DTH responses against TMEV after low doses of gamma-irradiation. Parental C57BL/6 animals remain resistant after similar pretreatment. Thus low-dose irradiation elicits a "latent" susceptibility to TMEV-IDD in some, but not all, resistant mice. Adoptively transferred spleen cells from syngeneic, unirradiated donors reconfer resistance on irradiated, infected B6D2F1 hybrids and reduce DTH responsiveness against TMEV, suggesting a protective role for a radiation-sensitive splenic population(s). The closely related C57BL/6 and C57BL/10 strains differ with respect to intrinsic and latent susceptibility.

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PubMed1984

Genetic analysis of susceptibility to Theiler's virus-induced demyelinating disease in mice.

Genetic control of resistance and susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in mice was examined. Mice derived from various crosses between susceptible SJL (S) and resistant C57BL/6 (B6) strains allowed determination of the relative susceptibility contributed by H-2 and non-H-2 genes, as well as allowing segregation of H-2 linked genes. Six of 39 B6SF1 hybrid progeny developed disease, suggesting several possibilities--resistance is dominant and susceptibility recessive but with incomplete penetrance, the incidence of disease is dose dependent and is dictated by the number of "susceptible/resistant" alleles present at one or more loci, or some combination of the two. Data involving the progeny from the B6SF1 hybrids mated to the S parental strain indicated the involvement of more than one locus. The strong correlation between the number of H-2s haplotypes and the incidence of demyelinating disease suggested that at least one of the genes was linked to the H-2 complex; however, other independently segregating (unlinked) loci strongly affected the disease incidence among H-2 identical animals. A gene or genes from the S background was also associated with enhanced virus growth or diminished virus clearance in the central nervous system (CNS). Overall, the observations support a gene dosage model for susceptibility that relates disease incidence to the total number of S alleles at both H-2 and non-H-2 loci.

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PubMed1981

Reconstitution of Ir genes, Ia antigens, and mixed lymphocyte reaction determinants by gene complementation.

By using clones of murine T cells reactive with alloantigens as well as soluble antigens, it has been possible to demonstrate that Ia antigens, Ir gene phenomena (defined as the ability of immune T cells to recognize antigen), and mixed lymphocyte reaction (MLR)-stimulating determinants encoded within the I-A subregion are different manifestations associated with same product. These studies utilized the I-Ab mutant mouse B6.C-H-2bm (bm12), whose defect in the normal expression of the cell surface products of the I-Ab subregion can be partially circumvented through trans-complementation by deriving hybrids between bm12 and mice expressing normal I-A subregion products. Such mice [e.g., (bm12 X B10.A)F1] express several serologically normal I-Ab products but have defects in certain I-A subregion gene products normally expressed on cells of H-2a X H-2b heterozygote mice that are used as restricting elements for antigen recognition by antigen-reactive T cell clones or recognized as alloantigens by alloreactive T cell clones. This defect in cell surface expression of certain normal I-Ab products on the mutant bm12 cells has allowed us to suggest that there exist trans-complementing products on H-2a X H-2b heterozygote mice consisting of Ab alpha Ak beta and Ak alpha Ab beta that restrict antigen recognition by cloned T cells, stimulate MLR responses by cloned T cells, and react with certain anti-Ia antisera.

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PubMed1981

Genetic control of the immune response to haemoglobin. III. Variant A beta (bm12) but not Ae (D2.GD) Ia polypeptides alter immune responsiveness towards the alpha -subunit of human haemoglobin.

Mice bearing the I-A subregion mutation bm12 were immunized and challenged with the alpha -subunit of human adult haemoglobin. Under conditions in which parental B6/Kh mice respond, B6.C-H-2bm12 mice are inhibited nearly 100% in their ability to respond to challenge to the alpha-chain of haemoglobin. D2.GD mice which express a variant Ae (E beta) polypeptide of the I-E subregion can respond as well as B10.D2 mice to both subunits (alpha- and beta-) of haemoglobin. These observations as well as other genetic mapping data confirm the I-A mapping of alpha -chain-specific Ir genes and extend the genetic fine mapping to the A beta gene within the I-A subregion or a combinatorial Ia determinant generated by an interaction of A alpha and A beta. In addition they implicate the Ia.8 specificity in determining immune responsiveness to alpha -chain determinants.

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PubMed1980

Ir gene testing in H-2 mutants.

Four different C57BL/6 mutants, each with a mutation presumably in the H-2Kb locus, were studied to determine whether the mutations had affected Ir gene function. When tested with the antigens, (TG)-A-L, ovalbumin (OA), and lactic dehydrogenase (LDHB), there was no difference in the antibody response of the mutants when compared to the parental C57BL/6 strain and there was also no difference in the response to the histocompatibility H-Y antigen. The responses to these antigens have been mapped, wholly or partially in the K-IA, IA or IB subregions and therefore the identical response of parent and mutants may provisionally exclude H-2Kb as a site of Ir gene function for the four antigens tested. In addition, the BALB/c-dm2 mutant, a mutation in the H-2Ld locus, gave identical responses to the parental BALB/cKh strain.

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PubMed1977

Mutation in a new H-2-associated histocompatibility gene closely linked to H-2D.

Sequential precipitations of soluble BALB/c antigen with antisera detecting private and public H-2 specificities indicated three distinct classes of molecules of 45,000 mol wt. However, only two of these classes of molecules were detectable in antigen from the loss mutant, BALB/c-H-2db. The class of molecules, detectable in the wild-type strain but missing in the mutant, does not bear private specificities but does react with an antiserum detecting H-2 public specificities. Absorption in mutant mice of the antiserum to public specificities, left antibodies specific for the antigen detectable in BALB/c but not BALB/c-H-2db. Genetic mapping studies using this specific antiserum indicated that the antigenic loss of this mutant is in a gene which maps in or close to the H-2D region, separable from the H-2K, S, G, Qa-2, and Tla regions.

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PubMedDate not supplied

Induction of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in genetically resistant mice.

Theiler's murine encephalomyelitis virus-induced demyelinating disease, a murine model for multiple sclerosis, is the result of persistent infection which leads to a T cell-mediated immunopathology. Susceptible strains develop virus-specific DTH responses while resistant strains do not, and this response has been proposed as the basis for inflammation and demyelination. (C57BL/6 x DBA/2)F1 hybrid animals, normally resistant to TMEV-induced demyelinating disease, become susceptible when treated in vivo prior to infection with low dose cyclophosphamide. Comparable pretreatment of other resistant animals, C57BL/6 and CB6 (BALB/c x C57BL/6) F1 hybrids, does not render them susceptible (despite the H-2 identity of CB6F1 and B6D2F1 hybrids). Thus the "latent" susceptibility in B6D2F1 hybrids must be attributed to non-H-2 genes from the susceptible D2 parent. Resistance can be restored to CY-treated B6D2F1 animals by the adoptive transfer of splenic cells (including T cell enriched populations) from non-CY-treated donors. Resistance to TMEV-IDD in these animals, therefore, may involve active inhibition of a "latent" disease susceptibility.

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