Faculty Bibliography

Resistance to neoplasia caused by radiation-induced leukemia virus (RadLV) is mediated by gene(s) in the H-2D region of the major histocompatibility complex. The previous observation that rapid increases in cellular synthesis and cell-surface expression of H-2 antigens are detectable immediately after virus inoculation has suggested that altered expression of H-2 antigens may play a significant role in the mechanism(s) of host defense to virus infection. This concept is supported by the following observations. First, cell-mediated immunity against RadLV transformed or infected cells can be detected with ease when H-2-positive target cells are used in the cell-mediated lympholysis (CML) assay. (Although RadLV transformed cells obtained from overtly leukemic animals and maintained in tissue culture are H-2 negative, these cells can regain their H-2 phenotype by in vivo passage in normal animals. The H-2-negative cells are poor targets in a CML assay.) Second, resistant mice develop greater numbers of effectors when infected with RadLV than do susceptible mice. Third, injection of normal (uninfected) thymocytes into syngeneic recipients of resistant or susceptible H-2 type does not stimulate a CML response. However, injection of RadLV infected thymocytes from resistant mice produces a vigorous CMI response, and such thymocytes elicit the strongest response at a time when both H-2 and viral antigen expression is elevated. By contrast, injection of infected thymocytes from susceptible mice, which express viral antigens, but low levels of H-2 antigens, does not stimulate a CML reaction. These findings may explain the easier induction of leukemia found by many investigators when virus is inoculated into neonatal mice and the preferential thymus tropism of some oncogenic type-C RNA virus. Cells expressing very low levels of H-2, such as thymocytes, may serve as permissive targets for virus infection because they lack an important component (H-2 antigens) of the dual or altered recognition signal required to trigger a defensive host immune response

Previous studies from this laboratory have mapped resistance and/or susceptibility to radiation-induced leukemia virus (RadLV)-induced neoplasia to the H-2D region. H-2 linked effects on virus replication can be detected subsequent to the initial virus infection, and clear-cut differences in numbers of virus infected thymus cells can be detected as early as 5 wk after RadLV inoculation. Rapid increases in cellular synthesis and cell surface expression of H-2 antigens are detectable immediately after virus inoculation. These changes have been studied by immunofluorescence, absorption, cell surface iodination followed by sodium dodecyl-sulfate-polyacrylamide gel electrophoresis, and two dimensional gel electrophoretic analysis of internally labeled lymphocyte proteins. Expression of H-2K molecules is significantly increased in cells of susceptible and resistant animals. However, significant increases in expression of H-2D antigens occurs only on thymus cells from resistant strains (H-2Dd). Transformed cells of resistant and susceptible H-2 haplotypes adapted to tissue culture lack detectable H-2 antigens as determined by serological absorption studies. It is argued that altered expression of H-2 antigens plays a very significant role in the mechanism of host defense to virus infection

The role of H-2-linked genes in controlling resistance to murine leukemia viruses has been studied by measuring the cell-mediated immune response of F1 hybrid mice (between AKR and various C3H and C57BL/10 derived, H-2 congenic strains) to an AKR tumor cell line, BW5147. The studies have shown that the ability to generate a primary or secondary cell-mediated response to an AKR tumor cell antigenic determinant is under H-2 linked control. The locus determining CML responsiveness maps in the I-J subregion. Nonresponsiveness is associated with the H-2q/k and H-2b/k hybrid genotypes, whereas responsiveness is associated with the H-2k/k homozygous genotype. Nonresponsiveness may result from (a) dominant suppression; (b) recessive responsiveness; or (c) an alternate mechanism not yet understood. This type of control may be one of several H-2-associated mechanisms of defense against virus-induced neoplasms

A single locus, tentatively denoted Srlv-1 (susceptibility to radiation leukemia virus [RadLV]-1), confers dominant susceptibility to RadLV-induced leukemogenesis. Srlv-1 is not linked to H-2, and appears to be distinct from Fv-1 and Fv-2. Preliminary data suggest that Srlv-1 affected virus proliferation. A striking feature of this system is that Srlv-1 overrides the protection afforded by the H2D-associated dominant resistance to RadLV-induced neoplasia

Resistance to radiation leukemia virus-induced leukemogenesis is associated with the H-2D region of the H-2 complex, or with closely linked loci. The H-2Dd allele confers resistance ot the disease, while the H-2D-Q and H-2Ds alleles are associated with susceptibility. It is not clear whether Ir genes, or an alternative mechanism are responsible for the observed H-2-linked resistance to the disease