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Influence of the Major Histocompatibility Complex on Tumor Regression and Immunity in Chickens
Influence of the Major Histocompatibility Complex on Tumor Regression and Immunity in Chickens L. W. SCHIERMAN Department of Avian Medicine, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30605 W. M. COLLINS Department of Animal and Nutritional Sciences, University of New Hampshire, Durham, New Hampshire 03824
ABSTRACT A number of studies show that major histocompatibility complex (MHC) genes control host immune responses to viral-induced chicken tumors. The MHC gene-controlled responses to malignant neoplasms caused by Rous sarcoma virus, lymphoid leukosis virus and Marek's disease virus are reviewed. Genes that determine regression of Rous sarcomas and resistance to development of lethal Marek's disease lymphomas appear to map within the B-F region of the MHC. In some cases, genetic complementation of both MHC genes and non-MHC genes may be responsible for regression of tumors. Metastasis of Rous sarcoma cells is also influenced by the host's MHC genotype. Background genes can modify the specific MHC gene effect on resistance to progressive growth of Rous sarcomas and Marek's disease lymphomas. Studies showing that MHC-restricted immunity may be important in cytotoxic T cell reactions to virus-infected and/or transformed chicken cells are discussed. The MHC-restricted cytotoxicity, whereby the T cells and target cells must share one MHC haplotype for in vitro killing to occur, suggests that the T cells have receptors that recognize virus-altered self MHC antigens. This may be an important immune surveillance mechanism for limiting the proliferative growth of virus-induced tumors in chickens. (Key words: major histocompatibility complex genes, Rous sarcoma, Marek's disease lymphoma, tumor immunity, major histocompatibility-restricted cytotoxicity) 1987 Poultry Science 66:812-818 INTRODUCTION
A considerable amount of research relating to major histocompatibility complex (MHC) gene control of immunity to tumors in chickens has been carried out in the past decade. This research has involved the study of tumors caused by both ribonucleic acid viruses and deoxyribonucleic acid viruses. The importance of the MHC genotype of the host for immune responses to virus-induced tumors has been well documented in a number of laboratories. For this review, studies will be discussed which pertain to MHC gene control of tumor regression as well as to the role of MHC gene products in the recognition and killing of tumor cells. ASSOCIATION OF MAJOR HISTOCOMPATIBILITY COMPLEX GENOTYPE WITH TUMOR REGRESSION
In general, the regression of virus-induced tumors represents an immune response against antigens expressed on the surface of the transformed cells. Therefore, meaningful studies pertaining to tumor regression in chickens can only be performed with animals whose cells are sus-
ceptible to infection and transformation by the virus. Resistance to infection by avian leukosissarcoma viruses is controlled by non-MHC genes at several different loci (Crittenden, 1975). Thus, tumor progression occurs in chickens whose cells are genetically susceptible to infection and whose immune response is unable to prevent continued proliferation of the transformed cells. The terms "progressor" and "regressor" are used to designate the phenotypic and genotypic classification ofan animal relative to the presence or absence of a proliferative lethal tumor. Rous Sarcomas. The Rous fowl sarcoma and its causative viral agent have been extensively studied by cancer research workers and molecular biologists. This avian neoplasm was first described by Peyton Rous in the early part of this century (Rous, 1910). Although the growth pattern of Rous sarcomas (i.e., progressive or regressive) was already known to be a heritable trait (Gyles and Brown, 1971; Carte etal, 1972) two independent research groups simultaneously reported in 1977 that this pattern is associated with the MHC genotype of the host (Collins et
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(Received for publication January 7, 1987)
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regression lies within the B-F region, or in a region closely linked to it, but not in the B-G region (Collins and Briles, 1980). Similar findings were obtained from studies conducted with the Prague lines (Plachy and Benda, 1981). Subsequently, tests at Iowa State University with birds considered to be MHC recombinants suggested that both B-F and B-L region genes control regression of RSV-induced tumors (Birkmeyer and Nordskog, 1982). Investigations in which different strains of RSV were used to induce the tumors revealed that MHC gene-controlled regression was clearly related to virus strain. Regressor and progressor phenotypes were reversed among birds of certain MHC genotypes when the RSV was of another strain belonging to the same antigenic subgroup (McBride et al., 1981). These findings suggested that immune recognition of RSV-induced tumors is highly specific and comparable to the marked discrimination between closely related antigens as found for MHC-controlled immune responses in the mouse. This concept is supported by the additional finding that different patterns of tumor growth occurred in inbred lines of chickens inoculated with separate isolates of the same strain (B77) of RSV (Cutting et al., 1981b). Results of other studies indicate that MHC gene-controlled responses to Rous sarcomas may also be associated with the subgroup of the virus used to induce the tumors (Nordskog and Gebriel, 1983; Brown et al., 1984). This would suggest that MHC gene-controlled responses can be against different types of tumor antigens or possibly against both tumor antigens and viral antigens. It may be that, in addition to anti-tumor cell immunity, heightened immunity to RSV could also retard the progressive development of tumors induced by the virus. Another aspect of MHC gene control of Rous sarcoma development is that genetic complementation may account for tumor regression in certain circumstances. This suggests that appropriate gene products from at least two separate loci must be present for expression of the regressor phenotype. Studies by Cutting et al. (1981a) revealed that the F, offspring from related inbred lines regressed Rous sarcomas whereas progressive tumor growth was found with birds of both the G-Bl (Bl3/B13) and G-B3 (Bl5/B15) parental lines. Findings obtained with offspring from backcrossing the F, birds to G-B1 and G-B 3 birds indicated that genetic complementation resulting in tumor regression oc-
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al., 1977; Schierman et al., 1977). Subsequent studies by others have confirmed these results (Gebriel era/., 1979; Plachy etal., 1979; Bacon etal., 1981;NordskogandGebriel, 1983). Findings pertaining to genetic control of immune responses to Rous sarcomas have recently been reviewed in detail by Collins and Zsigray (1984). Studies at the University of New Hampshire with F 2 generation birds derived from crossing inbred lines 6, (MHC genotype B2IB2) and 15, (MHC genotype B5IB ) conclusively showed that regression of tumors induced by wing web inoculation of Rous sarcoma virus (RSV) was associated with the B2 haplotype (Collins et al., 1977). The percentage of B2/B2, B2/B5, and B5I B5 birds dying with progressively growing tumors by 70 days post-inoculation was 5, 26, and 93%, respectively. Similar results were obtained at New York Medical College when backcross progeny derived from inbred lines G-Bl and G-B2 (developed from a common partially inbred line) were inoculated with RSV. The MHC genotypes of G-Bl and G-B2 chickens, which have been redesignated in accordance with a common MHC nomenclature system (Briles et al., 1982a), are B]3/B13 and B6/B6, respectively. Of 90 backcross progeny, from B6/B13 Fj females mated to a G-Bl male, tumor regression occurred in 4% of the B]3/B]3 offspring and 92% of the B6/B13 offspring. Thus, in this case, Rous sarcoma regression was clearly associated with inheritance of the B6 haplotype from the dams (Schierman et al., 1977). In a study with the noninbred New Hampshire Line UNH 105, where segregation was occurring for Haplotypes B23, B24, and B26, a significant MHC genotype effect upon Rous sarcoma regression was found (Collins et al., 1979). However, since the effect was not as pronounced as in the earlier studies with inbred Leghorns and their crosses, the results suggested that background genes also had an influence on tumor growth. The contribution of non-MHC genes in the host's response to Rous sarcomas has been confirmed and extended by other studies (Collins et al, 1980; Brown, 1982; Gebriel and Nordskog, 1983; Gilmour et al., 1986). Experiments designed to determine the specific region of the MHC (B-F, B-G or B-L) in which the genes controlling Rous sarcoma regression are located have been carried out in three laboratories. In tests with MHC recombinants produced by W. E. Briles, it was determined that a gene influencing Rous sarcoma
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virus caused mortality due to erythroblastosis that was significantly higher fori? IB5 birds than for B2IB2 or B2/B5 birds. In one experiment, the B5/B5 birds also had a significantly higher incidence of hemangiocarcinomas than birds of the other two B genotypes. Marek's Disease Lymphomas. Because studies concerning the association of MHC genotype to Marek's disease (MD) susceptibility are reviewed in the accompanying paper presented by L. D. Bacon at this symposium, only a limited summary is given in this report. The first firm evidence that resistance to development of Marek's disease virus (MDV)-induced lymphomas was associated with MHC genotype was obtained by Hansen et al. (1967). Birds carrying the fi21 haplotype were found to be more resistant to MD than birds carrying the B 19 haplotype. Of considerable interest were subsequent findings with two lines of chickens developed at Cornell University by selection for either resistance or susceptibility to MD (Cole, 1968). Blood typing results showed that birds of the MD-resistant line (Line N) were homozygous B1XIB2X and most birds of the MDsusceptible line (Line P) were B[9/B19. Backcross offspring derived from B[9/B21 F, birds mated to B]9/B19 Line P birds were then challenged with the JM strain of MDV. The incidence of MD for Bi9/Bi9 and Bi9/B2] offspring was 69.7 and 8.6%, respectively (Briles et al., 1977). Thus, inheritance of the B2> haplotype conferred a marked degree of resistance to tumors caused by MDV. Similar findings were reported the previous year by Longenecker et al. (1976) who tested MD resistance in several F 2 populations at Edmonton and Ottawa. Their results showed that B 2 '/B 21 and B2/B2] birds were significantly more resistant to development of MD lymphomas than were B2IB2 birds. However, additional studies by others revealed that the influence of the B2 and B21 haplotypes may not be the same with regard to MD resistance in populations having a different genetic background. Of five heterozygous classes which carried the B2[ haplotype in a single cross Leghorn flock, B2IB2{ birds had a significantly lower incidence of MD than the other four classes that carried B2X along with a different B haplotype (Briles et al., 1982b). The authors concluded that certain B haplotypes present in parent stocks may complement each other in heterozygous crossline birds. The relevance of background genes on the expression of MHC genotype-associated resistance to MD was demonstrated further in a study
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curred between both MHC and non-MHC genes. Evidence of genetic complementation, or possibly a heterosis effect, was obtained in a study with the noninbred New Hampshire Line UNH 105 where Rous sarcoma regression was significantly higher for B23/B26 heterozygotes than for either B23/B23 or B26/B26 homozygotes (Brown etai, 1982). The MHC genes associated with regression of Rous sarcomas also appear to restrict metastatic spread of the tumors. This was suggested by the initial results obtained at New Hampshire with F 2 birds from Lines 6, and 15, (Collins et al., 1977). In a subsequent experiment with this same stock, 201 of 1144 birds developed confirmed metastatic lesions. For B2IB2 and B5/B5 hosts, mortality was 8 and 93% and metastatic frequency was 32 and 58%, respectively (Collins et al., 1986). In another study with B5IB5 hosts from a Leghorn-New Hampshire F 2 population, the incidence of metastases was significantly lower (Collins et al., 1985), which suggested that non-MHC genes may affect the spread of RSV-induced tumors. Results of a study by Bacon et al. (1981) with inbred Leghorn Lines 63 and 151 and their F 4 generation offspring also indicated that MHC genes controlling regression of primary RSV-induced tumors in the wing web play a major role in inhibiting the development of metastatic tumors at other sites. Thus, it seems likely that the same immune mechanism is involved in these two events. A finding that may be of importance with regard to elucidating the mechanism of immune recognition and regression of Rous sarcomas was recently reported by Powell et al. (1986). Examination of Rous sarcomas by immunofluorescence revealed that tumor cells in regressing sarcomas were positive for Class II (B-L) MHC antigens whereas tumor cells from progressing sarcomas were negative for these antigens. The determination of Class I (B-F) MHC antigen expression on Rous sarcoma cells from progressor and regressor birds may also be of value in the study of tumor immunity. The variable expression of both classes of MHC antigens on tumor cells relative to tumorogenicity in other species is well documented (Doherty et al., 1984). Lymphoid Leukosis. The influence of MHC genotype on susceptibility to lymphoid leukosis appears to be markedly lower than that found for Rous sarcomas. A study by Bacon et al. (1981) with F 4 and F5 generation chickens derived from Leghorn Lines 63 and 15, showed that inoculation of RAV-1 lymphoid leukosis
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MAJOR HISTOCOMPATIBILITY COMPLEX-RESTRICTED IMMUNITY TO VIRUS INFECTED AND TRANSFORMED CELLS
Although the production of antibodies with the potential to neutralize oncogenic viruses may be involved in limiting development and growth of tumors in chickens, it appears that the primary mechanism responsible for tumor regression involves participation of cytotoxic T cells (Wainberg and Phillips, 1976; Calnek, 1980). That MHC antigens play an essential role in recognition and killing of virus-infected cells by specifically immune T cells was first suggested by the findings of Zinkernagel and Doherty (1974a) with mice. In an in vitro assay, effector spleen cells from mice infected with lymphocytic choriomeningitis virus (LCMV) killed LCMVinfected target cells only when the effector cells and target cells shared at least one MHC antigen. Additional studies with the LCMV system suggested to these workers that cytotoxic T cells from infected hosts may have receptors for virusaltered-self MHC antigens, or that there is recognition by two T cell populations: one with receptors specific for self MHC antigens and the other with receptors specific for viral antigens (Zinkernagel and Doherty, 1974b). On the basis of more recent studies, including cloning of the T cell receptor genes, it appears that a single receptor with specificity for altered-self MHC antigens is involved in the MHC-restricted cytotoxicity phenomenon (Marrack and Kappler, 1986).
A number of studies have shown that, in addition to virus-infected cells, killing of certain mouse tumor cells is also MHC-restricted (Doherty et al., 1984). An indication that immunity to Rous sarcomas in chickens may be under similar control was obtained in a study by Wainberg etal. (1974). Spleen cells from RSV-inoculated outbred birds generally showed a higher degree of reactivity against their own (autochthonous) Rous tumor cells than against Rous tumor cells from other birds. Recent studies at the University of Georgia have clearly shown that MHC-restricted cytotoxicity exists with spleen cells from reticuloendotheliosis virus (REV)-infected chickens (Maccubbin and Schierman, 1986). Cells from three REV-transformed cell lines were used as targets in an in vitro chromium release assay to measure cytotoxicity of the spleen cells. The cell lines were established from bone marrow cells of REV-infected G-Bl (fl13/B13), GB2 (B6/B6), and F, (B6/B13) chickens. The MHC-restricted cytotoxicity was demonstrated with effector spleen cells from REV-inoculated F 2 generation birds because significant lysis occurred only when the effector cells and target cells shared at least one MHC antigen. Specific cytotoxicity was highest when the F, derived target cells were used with F! spleen cells. This finding suggests that the heterozygous birds had two different populations of immune T cells: one with receptors for REV-altered B 6 antigens and the other with receptors for REV-altered B 13 antigens. Of interest in this regard is that Doherty and Zinkernagel (1975) found an enhanced T cell responsiveness in virus-infected F, mice and proposed that this observation provided a mechanistic basis for an evolutionary advantage of heterozygosity for MHC genes. The MHC-restricted reactivity against REVtransformed chicken cells was found to be directed against a virus-induced antigen (Maccubbin and Schierman, 1986). Recently, virus specific killing of syngeneic REV-transformed cells was reported by Weinstock and Schat (1986). With regard to Marek's disease, results obtained at two laboratories indicated that MHCrestricted killing of MDV-transformed target cells was not evident (Schat et al., 1982; Powell et al., 1983). Instead, spleen cells from MDVinoculated birds appeared to have specificity for normal allogeneic cells. A possible explanation for these findings is that the syngeneic target cells used, which were selected for optimal in vitro growth potential, may not have possessed
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with eight different B congenic lines (Abplanalp et al., 1985). These lines, developed by several generations of backcrossing to the same inbred line, are homozygous for different B haplotypes but have a common genetic background. From challenge studies with three different strains of MDV, it was found that B2IB2 birds ranked slightly above B2l/B21 birds in resistance to MD lymphomas. This was particularly evident when a highly virulent strain (RB-1B) of MDV was used to infect the birds. Thus, MHC gene-controlled resistance to MD lymphomas appears to involve several factors including interaction with non-MHC genes, and possibly, pathogenicity of the tumor-inducing virus. Similar to the findings with Rous sarcomas, studies with MHC-recombinant chickens indicate that genes within the B-F region or closely linked to it, but not the B-G region, are responsible for expression of resistance or susceptibility to MD (Briles etal., 1983; Plachy et al, 1984).
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defined MHC genotypes may well provide new insight into the mechanisms associated with immune reactions against malignant tumor cells. REFERENCES Abplanalp, H., K. A. Schat, and B. W. Calnek, 1985. Resistance to Marek's disease of congenic lines differing in major histocompatibility haplotypes to 3 virus strains. Pages 347-358 in: International Symposium on Marek's Disease. B. W. Calnek and J. L. Spencer, ed. Am. Assoc, of Avian Pathol., Kennet Square, PA. Bacon, L. D., R. L. Witter, L. B. Crittenden, A. Fadley, and J. Motta, 1981. B-haplotype influence on Marek's disease, Rous sarcoma, and lymphoid leukosis virusinduced tumors in chickens. Poultry Sci. 60:11321139. Birkmeyer, R. C , and A. W. Nordskog, 1982. Control of Rous sarcoma virus regression by the chicken major histocompatibility complex. Page 71 in: Proc. 18th Int. Conf. Blood Groups and Biochem. Polymorphisms, Ottawa, Canada. (Abstr.) Briles, W. E., R. W. Briles, D. L. Pollock, and M. Pattison, 1982b. Marek's disease resistance of B (MHC) heterozygotes in a cross of purebred Leghorn lines. Poultry Sci. 61:205-211. Briles, W. E., R. W. Briles, R. E. Taffs, and H. A. Stone, 1983. Resistance to a malignant lymphoma in chickens is mapped to subregion of major histocompatibility (fl) complex. Science 219:977-979. Briles, W. E., N. Bumstead, D. L. Ewert, D. G. Gilmour, J. Gogusev, K. Hala, C. Koch, B. M. Longenecker, A. W. Nordskog, J.R.L. Pink, L. W. Schierman, M. Simonsen, A. Toivanen, P. Toivanen, O. Vainio, and G. Wick, 1982a. Nomenclature for chicken major histocompatibility (5) complex. Immunogenetics 15:441^-47. Briles, W. E., H. A. Stone, and R. K. Cole, 1977. Marek's disease: Effects of B histocompatibility alloalleles in resistant and susceptible chicken lines. Science 195:193-196. Brown, D. W., 1982. Major histocompatibility complex (MHC) vs. non-MHC influences on response to RSVinduced tumors in chickens. Ph.D. Diss. Univ. New Hampshire, Durham, NH. Brown, D. W., W. M. Collins, and W. E. Briles, 1984. Specificity of B genotype response to tumors induced by each of three subgroups of Rous sarcoma virus. Immunogenetics 19:141-147. Brown, D. W., W. M. Collins, P. H. Ward, and W. E. Briles, 1982. Complementation of major histocompatibility haplotypes in regression of Rous sarcoma virusinduced tumors in noninbred chickens. Poultry Sci. 61:409-413 Calnek, B. W., 1980. Marek's disease virus and lymphomas. Pages 103-143 in: Oncogenic Herpesviruses. Vol. I. F. Rapp.ed. CRC Press Inc., Boca Raton, FL. Carte, I. F., J. H. Smith, C. R. Weston, and T. F. Savage, 1972. Immunogenetics and regression of RSV (RAV1) wing-web tumors in chickens. Poultry Sci. 51:1792. (Abstr.) Cole, R. K., 1968. Studies on genetic resistance to Marek's disease. Avian Dis. 12:9-28. Collins, W. M., and W. E. Briles, 1980. Response of two B (MHC) recombinants to Rous sarcoma virus-induced tumors. J. Int. Soc. Animal Blood Group Res.
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the appropriate altered-self antigen configuration. This configuration could, however, be similar to "unaltered" MHC alloantigens so that the allogeneic cells were lysed due to a crossreactive recognition by receptors on the immune T cells. Such cross-reactivity patterns have been found with certain clones of cytotoxic T cells from mice (Guimezanes et al., 1982). An indication that MHC-restricted immunity may occur in MDV-infected or MDV-transformed cells or both has recently been obtained from both in vivo and in vitro studies at the University of Georgia. Immunizations with cells from virus-nonproducer MD lymphoblastoid cell lines, established from Line G-Bl and Line G-B2 transplantable MD lymphomas, were found to preferentially protect syngeneic (i.e., histocompatible) birds subsequently challenged with the highly lethal syngeneic MD lymphomas (Schierman, 1984). Inoculation of the virusnonproducer lymphoblastoid cells also protected against primary MDV-induced lymphomas and inhibited virus shedding among syngeneic and semisyngeneic (Fj) recipients, but not allogeneic (i.e., histoincompatible) recipients (Schierman, 1985). Additional studies showed that MDVcaused pathogenesis of lymphoid organs and viremia were preferentially reduced in syngeneic and semisyngeneic recipients of the lymphoblastoid cells (Tseng et al, 1986). One interpretation of these results is that the immune protection observed could have been due to an in vivo MHC-restriction mechanism whereby the host T cells recognized MDV-altered-self MHC antigens on the immunizing cells. Subsequent studies with F 2 birds have clearly shown that MHC-restricted cytotoxicity did occur when cells from a Line G-B2-derived MD lymphoblastoid cell line were used in an in vitro assay (Tseng and Schierman, unpublished data). Furthermore, cells from this line were found to have the greatest degree of immunogenicity, as measured by the in vitro cytotoxicity assay, when inoculated into syngeneic and semisyngeneic birds. This finding strongly suggests that MDV-transformed cells possess altered MHC antigens that are recognized by way of an immune surveillance mechanism in chickens that may normally provide a means of detecting and eliminating such cells. The concept of immunological surveillance of tumor cells, as it relates to the phenomenon of MHC-restricted cytotoxic T cell reactions, is discussed in a recent review (Doherty et al., 1984). Further studies with chickens of
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Differences in susceptibility to Marek's disease in chickens carrying two different B locus blood group alleles. Poultry Sci. 46:1268. (Abstr.) Longenecker, B. M., F. Pazderka, J. S. Gavora, J. L. Spencer, and R. F. Ruth, 1976. Lymphoma induced by herpesvirus: resistance associated with a major histocompatibility gene. Immunogenetics 3:401^-07. Maccubbin, D. A., and L. W. Schierman, 1986. MHC-restricted cytotoxic response of chicken T cells: expression, augmentation, and clonal characterization. J. Immunol. 136:12-16. Marrack, P., and J. Kappler, 1986. The antigen-specific, major histocompatibility complex-restricted receptor on T cells. Adv. Immunol. 38:1-30. McBride, R. A., J. A. Cutting, L. W. Schierman, F. R. Strebel, andD. H. Watanabe, 1981. MHC gene control of growth of avian sarcoma virus-induced tumours in chickens: a study of the role of virus strain. J. Immunogenet. 8:207-214. Nordskog, A. W., andG. M. Gebriel, 1983. Genetic aspects of Rous sarcoma-induced tumor expression in chickens. Poultry Sci. 62:725-732. Plachy, J., and V. Benda, 1981. Location of the gene responsible for Rous sarcoma regression in the B-F region of the B complex (MHC) of the chicken. Folia Biol. (Praha) 27:363-368. Plachy, J., K. Hala, and V. Benda, 1979. Regression of tumours induced by Rous sarcoma virus in different inbred lines of chickens. Folia Biol. (Praha) 25:335336. Plachy, J., V. Jurajda, and V. Benda, 1984. Resistance to Marek's disease is controlled by a gene within the B-F region of the chicken major histocompatibility complex in Rous sarcoma regressor or progressor inbred lines of chickens. Folia Biol. (Praha) 30:251-258. Powell, P. C , B. M. Mustill, and M. Rennie, 1983. The role of histocompatibility antigens in cell-mediated cytotoxicity against Marek's disease tumour-derived lymphoblastoid cell lines. Avian Pathol. 12:461—468. Powell, P. C , K. Hala, and G. Wick, 1987. Aberrant expression of B-L (la-like) antigens on tumour cells of regressing but not of progressing Rous sarcomas. In: Avian Immunology II. W. T. Weber and D. L. Ewert, ed. Alan R. Liss, Inc., New York, NY. (in press). Rous, P., 1910. A transmissible avian neoplasm. (Sarcoma of the common fowl). J. Exp. Med. 12:696-705. Schat, K. A., W. R. Shek, B. W. Calnek, andH. Abplanalp, 1982. Syngeneic and allogeneic cell-mediated cytotoxicity against Marek's disease lymphoblastoid tumor cell lines. Int. J. Cancer 29:187-194. Schierman, L. W., 1984. Transplantable Marek's disease lymphomas. II. Variable tumor immunity induced by different lymphoblastoid cells. J. Natl. Cancer Inst. 73:423-428. Schierman, L. W., 1985. Studies on tumor immunity induced by Marek's disease lymphoblastoid cells. Pages 295-305 in: Int. Symp. Marek's Disease. B. W. Calnek and J. L. Spencer, ed. Am. Assoc, of Avian Pathol., Kennett Square, PA. Schierman, L. W., D. H. Watanabe, and R. A. McBride, 1977. Genetic control of Rous sarcoma regression in chickens: linkage with the major histocompatibility complex. Immunogenetics 5:325-332. Tseng, C. K., O. J. Fletcher, and L. W. Schierman, 1986. Preferential protection against Marek's disease virusinduced pathogenesis by immunisation with syngeneic virus-nonproducer lymphoblastoid cells. Avian
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formed cell line target cells by spleen cells. In: Avian Immunology II. W. T. Weber and D. L. Ewert, ed. Alan R. Liss, Inc., New York, NY. (in press). Zinkernagel, R. M., and P. C. Doherty, 1974a. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248:701-702. Zinkernagel, R. M., and P. C. Doherty, 1974b. Immunological surveillance against altered self components by sensitized T lymphocytes in lymphocytic choriomeningitis. Nature 251:547-548.
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ABSTRACT A number of studies show that major histocompatibility complex (MHC) genes control host immune responses to viral-induced chicken tumors. The MHC gene-controlled responses to malignant neoplasms caused by Rous sarcoma virus, lymphoid leukosis virus and Marek's disease virus are reviewed. Genes that determine regression of Rous sarcomas and resistance to development of lethal Marek's disease lymphomas appear to map within the B-F region of the MHC. In some cases, genetic complementation of both MHC genes and non-MHC genes may be responsible for regression of tumors. Metastasis of Rous sarcoma cells is also influenced by the host's MHC genotype. Background genes can modify the specific MHC gene effect on resistance to progressive growth of Rous sarcomas and Marek's disease lymphomas. Studies showing that MHC-restricted immunity may be important in cytotoxic T cell reactions to virus-infected and/or transformed chicken cells are discussed. The MHC-restricted cytotoxicity, whereby the T cells and target cells must share one MHC haplotype for in vitro killing to occur, suggests that the T cells have receptors that recognize virus-altered self MHC antigens. This may be an important immune surveillance mechanism for limiting the proliferative growth of virus-induced tumors in chickens. (Key words: major histocompatibility complex genes, Rous sarcoma, Marek's disease lymphoma, tumor immunity, major histocompatibility-restricted cytotoxicity) 1987 Poultry Science 66:812-818 INTRODUCTION
A considerable amount of research relating to major histocompatibility complex (MHC) gene control of immunity to tumors in chickens has been carried out in the past decade. This research has involved the study of tumors caused by both ribonucleic acid viruses and deoxyribonucleic acid viruses. The importance of the MHC genotype of the host for immune responses to virus-induced tumors has been well documented in a number of laboratories. For this review, studies will be discussed which pertain to MHC gene control of tumor regression as well as to the role of MHC gene products in the recognition and killing of tumor cells. ASSOCIATION OF MAJOR HISTOCOMPATIBILITY COMPLEX GENOTYPE WITH TUMOR REGRESSION
In general, the regression of virus-induced tumors represents an immune response against antigens expressed on the surface of the transformed cells. Therefore, meaningful studies pertaining to tumor regression in chickens can only be performed with animals whose cells are sus-
ceptible to infection and transformation by the virus. Resistance to infection by avian leukosissarcoma viruses is controlled by non-MHC genes at several different loci (Crittenden, 1975). Thus, tumor progression occurs in chickens whose cells are genetically susceptible to infection and whose immune response is unable to prevent continued proliferation of the transformed cells. The terms "progressor" and "regressor" are used to designate the phenotypic and genotypic classification ofan animal relative to the presence or absence of a proliferative lethal tumor. Rous Sarcomas. The Rous fowl sarcoma and its causative viral agent have been extensively studied by cancer research workers and molecular biologists. This avian neoplasm was first described by Peyton Rous in the early part of this century (Rous, 1910). Although the growth pattern of Rous sarcomas (i.e., progressive or regressive) was already known to be a heritable trait (Gyles and Brown, 1971; Carte etal, 1972) two independent research groups simultaneously reported in 1977 that this pattern is associated with the MHC genotype of the host (Collins et
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(Received for publication January 7, 1987)
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regression lies within the B-F region, or in a region closely linked to it, but not in the B-G region (Collins and Briles, 1980). Similar findings were obtained from studies conducted with the Prague lines (Plachy and Benda, 1981). Subsequently, tests at Iowa State University with birds considered to be MHC recombinants suggested that both B-F and B-L region genes control regression of RSV-induced tumors (Birkmeyer and Nordskog, 1982). Investigations in which different strains of RSV were used to induce the tumors revealed that MHC gene-controlled regression was clearly related to virus strain. Regressor and progressor phenotypes were reversed among birds of certain MHC genotypes when the RSV was of another strain belonging to the same antigenic subgroup (McBride et al., 1981). These findings suggested that immune recognition of RSV-induced tumors is highly specific and comparable to the marked discrimination between closely related antigens as found for MHC-controlled immune responses in the mouse. This concept is supported by the additional finding that different patterns of tumor growth occurred in inbred lines of chickens inoculated with separate isolates of the same strain (B77) of RSV (Cutting et al., 1981b). Results of other studies indicate that MHC gene-controlled responses to Rous sarcomas may also be associated with the subgroup of the virus used to induce the tumors (Nordskog and Gebriel, 1983; Brown et al., 1984). This would suggest that MHC gene-controlled responses can be against different types of tumor antigens or possibly against both tumor antigens and viral antigens. It may be that, in addition to anti-tumor cell immunity, heightened immunity to RSV could also retard the progressive development of tumors induced by the virus. Another aspect of MHC gene control of Rous sarcoma development is that genetic complementation may account for tumor regression in certain circumstances. This suggests that appropriate gene products from at least two separate loci must be present for expression of the regressor phenotype. Studies by Cutting et al. (1981a) revealed that the F, offspring from related inbred lines regressed Rous sarcomas whereas progressive tumor growth was found with birds of both the G-Bl (Bl3/B13) and G-B3 (Bl5/B15) parental lines. Findings obtained with offspring from backcrossing the F, birds to G-B1 and G-B 3 birds indicated that genetic complementation resulting in tumor regression oc-
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al., 1977; Schierman et al., 1977). Subsequent studies by others have confirmed these results (Gebriel era/., 1979; Plachy etal., 1979; Bacon etal., 1981;NordskogandGebriel, 1983). Findings pertaining to genetic control of immune responses to Rous sarcomas have recently been reviewed in detail by Collins and Zsigray (1984). Studies at the University of New Hampshire with F 2 generation birds derived from crossing inbred lines 6, (MHC genotype B2IB2) and 15, (MHC genotype B5IB ) conclusively showed that regression of tumors induced by wing web inoculation of Rous sarcoma virus (RSV) was associated with the B2 haplotype (Collins et al., 1977). The percentage of B2/B2, B2/B5, and B5I B5 birds dying with progressively growing tumors by 70 days post-inoculation was 5, 26, and 93%, respectively. Similar results were obtained at New York Medical College when backcross progeny derived from inbred lines G-Bl and G-B2 (developed from a common partially inbred line) were inoculated with RSV. The MHC genotypes of G-Bl and G-B2 chickens, which have been redesignated in accordance with a common MHC nomenclature system (Briles et al., 1982a), are B]3/B13 and B6/B6, respectively. Of 90 backcross progeny, from B6/B13 Fj females mated to a G-Bl male, tumor regression occurred in 4% of the B]3/B]3 offspring and 92% of the B6/B13 offspring. Thus, in this case, Rous sarcoma regression was clearly associated with inheritance of the B6 haplotype from the dams (Schierman et al., 1977). In a study with the noninbred New Hampshire Line UNH 105, where segregation was occurring for Haplotypes B23, B24, and B26, a significant MHC genotype effect upon Rous sarcoma regression was found (Collins et al., 1979). However, since the effect was not as pronounced as in the earlier studies with inbred Leghorns and their crosses, the results suggested that background genes also had an influence on tumor growth. The contribution of non-MHC genes in the host's response to Rous sarcomas has been confirmed and extended by other studies (Collins et al, 1980; Brown, 1982; Gebriel and Nordskog, 1983; Gilmour et al., 1986). Experiments designed to determine the specific region of the MHC (B-F, B-G or B-L) in which the genes controlling Rous sarcoma regression are located have been carried out in three laboratories. In tests with MHC recombinants produced by W. E. Briles, it was determined that a gene influencing Rous sarcoma
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virus caused mortality due to erythroblastosis that was significantly higher fori? IB5 birds than for B2IB2 or B2/B5 birds. In one experiment, the B5/B5 birds also had a significantly higher incidence of hemangiocarcinomas than birds of the other two B genotypes. Marek's Disease Lymphomas. Because studies concerning the association of MHC genotype to Marek's disease (MD) susceptibility are reviewed in the accompanying paper presented by L. D. Bacon at this symposium, only a limited summary is given in this report. The first firm evidence that resistance to development of Marek's disease virus (MDV)-induced lymphomas was associated with MHC genotype was obtained by Hansen et al. (1967). Birds carrying the fi21 haplotype were found to be more resistant to MD than birds carrying the B 19 haplotype. Of considerable interest were subsequent findings with two lines of chickens developed at Cornell University by selection for either resistance or susceptibility to MD (Cole, 1968). Blood typing results showed that birds of the MD-resistant line (Line N) were homozygous B1XIB2X and most birds of the MDsusceptible line (Line P) were B[9/B19. Backcross offspring derived from B[9/B21 F, birds mated to B]9/B19 Line P birds were then challenged with the JM strain of MDV. The incidence of MD for Bi9/Bi9 and Bi9/B2] offspring was 69.7 and 8.6%, respectively (Briles et al., 1977). Thus, inheritance of the B2> haplotype conferred a marked degree of resistance to tumors caused by MDV. Similar findings were reported the previous year by Longenecker et al. (1976) who tested MD resistance in several F 2 populations at Edmonton and Ottawa. Their results showed that B 2 '/B 21 and B2/B2] birds were significantly more resistant to development of MD lymphomas than were B2IB2 birds. However, additional studies by others revealed that the influence of the B2 and B21 haplotypes may not be the same with regard to MD resistance in populations having a different genetic background. Of five heterozygous classes which carried the B2[ haplotype in a single cross Leghorn flock, B2IB2{ birds had a significantly lower incidence of MD than the other four classes that carried B2X along with a different B haplotype (Briles et al., 1982b). The authors concluded that certain B haplotypes present in parent stocks may complement each other in heterozygous crossline birds. The relevance of background genes on the expression of MHC genotype-associated resistance to MD was demonstrated further in a study
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curred between both MHC and non-MHC genes. Evidence of genetic complementation, or possibly a heterosis effect, was obtained in a study with the noninbred New Hampshire Line UNH 105 where Rous sarcoma regression was significantly higher for B23/B26 heterozygotes than for either B23/B23 or B26/B26 homozygotes (Brown etai, 1982). The MHC genes associated with regression of Rous sarcomas also appear to restrict metastatic spread of the tumors. This was suggested by the initial results obtained at New Hampshire with F 2 birds from Lines 6, and 15, (Collins et al., 1977). In a subsequent experiment with this same stock, 201 of 1144 birds developed confirmed metastatic lesions. For B2IB2 and B5/B5 hosts, mortality was 8 and 93% and metastatic frequency was 32 and 58%, respectively (Collins et al., 1986). In another study with B5IB5 hosts from a Leghorn-New Hampshire F 2 population, the incidence of metastases was significantly lower (Collins et al., 1985), which suggested that non-MHC genes may affect the spread of RSV-induced tumors. Results of a study by Bacon et al. (1981) with inbred Leghorn Lines 63 and 151 and their F 4 generation offspring also indicated that MHC genes controlling regression of primary RSV-induced tumors in the wing web play a major role in inhibiting the development of metastatic tumors at other sites. Thus, it seems likely that the same immune mechanism is involved in these two events. A finding that may be of importance with regard to elucidating the mechanism of immune recognition and regression of Rous sarcomas was recently reported by Powell et al. (1986). Examination of Rous sarcomas by immunofluorescence revealed that tumor cells in regressing sarcomas were positive for Class II (B-L) MHC antigens whereas tumor cells from progressing sarcomas were negative for these antigens. The determination of Class I (B-F) MHC antigen expression on Rous sarcoma cells from progressor and regressor birds may also be of value in the study of tumor immunity. The variable expression of both classes of MHC antigens on tumor cells relative to tumorogenicity in other species is well documented (Doherty et al., 1984). Lymphoid Leukosis. The influence of MHC genotype on susceptibility to lymphoid leukosis appears to be markedly lower than that found for Rous sarcomas. A study by Bacon et al. (1981) with F 4 and F5 generation chickens derived from Leghorn Lines 63 and 15, showed that inoculation of RAV-1 lymphoid leukosis
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MAJOR HISTOCOMPATIBILITY COMPLEX-RESTRICTED IMMUNITY TO VIRUS INFECTED AND TRANSFORMED CELLS
Although the production of antibodies with the potential to neutralize oncogenic viruses may be involved in limiting development and growth of tumors in chickens, it appears that the primary mechanism responsible for tumor regression involves participation of cytotoxic T cells (Wainberg and Phillips, 1976; Calnek, 1980). That MHC antigens play an essential role in recognition and killing of virus-infected cells by specifically immune T cells was first suggested by the findings of Zinkernagel and Doherty (1974a) with mice. In an in vitro assay, effector spleen cells from mice infected with lymphocytic choriomeningitis virus (LCMV) killed LCMVinfected target cells only when the effector cells and target cells shared at least one MHC antigen. Additional studies with the LCMV system suggested to these workers that cytotoxic T cells from infected hosts may have receptors for virusaltered-self MHC antigens, or that there is recognition by two T cell populations: one with receptors specific for self MHC antigens and the other with receptors specific for viral antigens (Zinkernagel and Doherty, 1974b). On the basis of more recent studies, including cloning of the T cell receptor genes, it appears that a single receptor with specificity for altered-self MHC antigens is involved in the MHC-restricted cytotoxicity phenomenon (Marrack and Kappler, 1986).
A number of studies have shown that, in addition to virus-infected cells, killing of certain mouse tumor cells is also MHC-restricted (Doherty et al., 1984). An indication that immunity to Rous sarcomas in chickens may be under similar control was obtained in a study by Wainberg etal. (1974). Spleen cells from RSV-inoculated outbred birds generally showed a higher degree of reactivity against their own (autochthonous) Rous tumor cells than against Rous tumor cells from other birds. Recent studies at the University of Georgia have clearly shown that MHC-restricted cytotoxicity exists with spleen cells from reticuloendotheliosis virus (REV)-infected chickens (Maccubbin and Schierman, 1986). Cells from three REV-transformed cell lines were used as targets in an in vitro chromium release assay to measure cytotoxicity of the spleen cells. The cell lines were established from bone marrow cells of REV-infected G-Bl (fl13/B13), GB2 (B6/B6), and F, (B6/B13) chickens. The MHC-restricted cytotoxicity was demonstrated with effector spleen cells from REV-inoculated F 2 generation birds because significant lysis occurred only when the effector cells and target cells shared at least one MHC antigen. Specific cytotoxicity was highest when the F, derived target cells were used with F! spleen cells. This finding suggests that the heterozygous birds had two different populations of immune T cells: one with receptors for REV-altered B 6 antigens and the other with receptors for REV-altered B 13 antigens. Of interest in this regard is that Doherty and Zinkernagel (1975) found an enhanced T cell responsiveness in virus-infected F, mice and proposed that this observation provided a mechanistic basis for an evolutionary advantage of heterozygosity for MHC genes. The MHC-restricted reactivity against REVtransformed chicken cells was found to be directed against a virus-induced antigen (Maccubbin and Schierman, 1986). Recently, virus specific killing of syngeneic REV-transformed cells was reported by Weinstock and Schat (1986). With regard to Marek's disease, results obtained at two laboratories indicated that MHCrestricted killing of MDV-transformed target cells was not evident (Schat et al., 1982; Powell et al., 1983). Instead, spleen cells from MDVinoculated birds appeared to have specificity for normal allogeneic cells. A possible explanation for these findings is that the syngeneic target cells used, which were selected for optimal in vitro growth potential, may not have possessed
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with eight different B congenic lines (Abplanalp et al., 1985). These lines, developed by several generations of backcrossing to the same inbred line, are homozygous for different B haplotypes but have a common genetic background. From challenge studies with three different strains of MDV, it was found that B2IB2 birds ranked slightly above B2l/B21 birds in resistance to MD lymphomas. This was particularly evident when a highly virulent strain (RB-1B) of MDV was used to infect the birds. Thus, MHC gene-controlled resistance to MD lymphomas appears to involve several factors including interaction with non-MHC genes, and possibly, pathogenicity of the tumor-inducing virus. Similar to the findings with Rous sarcomas, studies with MHC-recombinant chickens indicate that genes within the B-F region or closely linked to it, but not the B-G region, are responsible for expression of resistance or susceptibility to MD (Briles etal., 1983; Plachy et al, 1984).
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defined MHC genotypes may well provide new insight into the mechanisms associated with immune reactions against malignant tumor cells. REFERENCES Abplanalp, H., K. A. Schat, and B. W. Calnek, 1985. Resistance to Marek's disease of congenic lines differing in major histocompatibility haplotypes to 3 virus strains. Pages 347-358 in: International Symposium on Marek's Disease. B. W. Calnek and J. L. Spencer, ed. Am. Assoc, of Avian Pathol., Kennet Square, PA. Bacon, L. D., R. L. Witter, L. B. Crittenden, A. Fadley, and J. Motta, 1981. B-haplotype influence on Marek's disease, Rous sarcoma, and lymphoid leukosis virusinduced tumors in chickens. Poultry Sci. 60:11321139. Birkmeyer, R. C , and A. W. Nordskog, 1982. Control of Rous sarcoma virus regression by the chicken major histocompatibility complex. Page 71 in: Proc. 18th Int. Conf. Blood Groups and Biochem. Polymorphisms, Ottawa, Canada. (Abstr.) Briles, W. E., R. W. Briles, D. L. Pollock, and M. Pattison, 1982b. Marek's disease resistance of B (MHC) heterozygotes in a cross of purebred Leghorn lines. Poultry Sci. 61:205-211. Briles, W. E., R. W. Briles, R. E. Taffs, and H. A. Stone, 1983. Resistance to a malignant lymphoma in chickens is mapped to subregion of major histocompatibility (fl) complex. Science 219:977-979. Briles, W. E., N. Bumstead, D. L. Ewert, D. G. Gilmour, J. Gogusev, K. Hala, C. Koch, B. M. Longenecker, A. W. Nordskog, J.R.L. Pink, L. W. Schierman, M. Simonsen, A. Toivanen, P. Toivanen, O. Vainio, and G. Wick, 1982a. Nomenclature for chicken major histocompatibility (5) complex. Immunogenetics 15:441^-47. Briles, W. E., H. A. Stone, and R. K. Cole, 1977. Marek's disease: Effects of B histocompatibility alloalleles in resistant and susceptible chicken lines. Science 195:193-196. Brown, D. W., 1982. Major histocompatibility complex (MHC) vs. non-MHC influences on response to RSVinduced tumors in chickens. Ph.D. Diss. Univ. New Hampshire, Durham, NH. Brown, D. W., W. M. Collins, and W. E. Briles, 1984. Specificity of B genotype response to tumors induced by each of three subgroups of Rous sarcoma virus. Immunogenetics 19:141-147. Brown, D. W., W. M. Collins, P. H. Ward, and W. E. Briles, 1982. Complementation of major histocompatibility haplotypes in regression of Rous sarcoma virusinduced tumors in noninbred chickens. Poultry Sci. 61:409-413 Calnek, B. W., 1980. Marek's disease virus and lymphomas. Pages 103-143 in: Oncogenic Herpesviruses. Vol. I. F. Rapp.ed. CRC Press Inc., Boca Raton, FL. Carte, I. F., J. H. Smith, C. R. Weston, and T. F. Savage, 1972. Immunogenetics and regression of RSV (RAV1) wing-web tumors in chickens. Poultry Sci. 51:1792. (Abstr.) Cole, R. K., 1968. Studies on genetic resistance to Marek's disease. Avian Dis. 12:9-28. Collins, W. M., and W. E. Briles, 1980. Response of two B (MHC) recombinants to Rous sarcoma virus-induced tumors. J. Int. Soc. Animal Blood Group Res.
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the appropriate altered-self antigen configuration. This configuration could, however, be similar to "unaltered" MHC alloantigens so that the allogeneic cells were lysed due to a crossreactive recognition by receptors on the immune T cells. Such cross-reactivity patterns have been found with certain clones of cytotoxic T cells from mice (Guimezanes et al., 1982). An indication that MHC-restricted immunity may occur in MDV-infected or MDV-transformed cells or both has recently been obtained from both in vivo and in vitro studies at the University of Georgia. Immunizations with cells from virus-nonproducer MD lymphoblastoid cell lines, established from Line G-Bl and Line G-B2 transplantable MD lymphomas, were found to preferentially protect syngeneic (i.e., histocompatible) birds subsequently challenged with the highly lethal syngeneic MD lymphomas (Schierman, 1984). Inoculation of the virusnonproducer lymphoblastoid cells also protected against primary MDV-induced lymphomas and inhibited virus shedding among syngeneic and semisyngeneic (Fj) recipients, but not allogeneic (i.e., histoincompatible) recipients (Schierman, 1985). Additional studies showed that MDVcaused pathogenesis of lymphoid organs and viremia were preferentially reduced in syngeneic and semisyngeneic recipients of the lymphoblastoid cells (Tseng et al, 1986). One interpretation of these results is that the immune protection observed could have been due to an in vivo MHC-restriction mechanism whereby the host T cells recognized MDV-altered-self MHC antigens on the immunizing cells. Subsequent studies with F 2 birds have clearly shown that MHC-restricted cytotoxicity did occur when cells from a Line G-B2-derived MD lymphoblastoid cell line were used in an in vitro assay (Tseng and Schierman, unpublished data). Furthermore, cells from this line were found to have the greatest degree of immunogenicity, as measured by the in vitro cytotoxicity assay, when inoculated into syngeneic and semisyngeneic birds. This finding strongly suggests that MDV-transformed cells possess altered MHC antigens that are recognized by way of an immune surveillance mechanism in chickens that may normally provide a means of detecting and eliminating such cells. The concept of immunological surveillance of tumor cells, as it relates to the phenomenon of MHC-restricted cytotoxic T cell reactions, is discussed in a recent review (Doherty et al., 1984). Further studies with chickens of
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Differences in susceptibility to Marek's disease in chickens carrying two different B locus blood group alleles. Poultry Sci. 46:1268. (Abstr.) Longenecker, B. M., F. Pazderka, J. S. Gavora, J. L. Spencer, and R. F. Ruth, 1976. Lymphoma induced by herpesvirus: resistance associated with a major histocompatibility gene. Immunogenetics 3:401^-07. Maccubbin, D. A., and L. W. Schierman, 1986. MHC-restricted cytotoxic response of chicken T cells: expression, augmentation, and clonal characterization. J. Immunol. 136:12-16. Marrack, P., and J. Kappler, 1986. The antigen-specific, major histocompatibility complex-restricted receptor on T cells. Adv. Immunol. 38:1-30. McBride, R. A., J. A. Cutting, L. W. Schierman, F. R. Strebel, andD. H. Watanabe, 1981. MHC gene control of growth of avian sarcoma virus-induced tumours in chickens: a study of the role of virus strain. J. Immunogenet. 8:207-214. Nordskog, A. W., andG. M. Gebriel, 1983. Genetic aspects of Rous sarcoma-induced tumor expression in chickens. Poultry Sci. 62:725-732. Plachy, J., and V. Benda, 1981. Location of the gene responsible for Rous sarcoma regression in the B-F region of the B complex (MHC) of the chicken. Folia Biol. (Praha) 27:363-368. Plachy, J., K. Hala, and V. Benda, 1979. Regression of tumours induced by Rous sarcoma virus in different inbred lines of chickens. Folia Biol. (Praha) 25:335336. Plachy, J., V. Jurajda, and V. Benda, 1984. Resistance to Marek's disease is controlled by a gene within the B-F region of the chicken major histocompatibility complex in Rous sarcoma regressor or progressor inbred lines of chickens. Folia Biol. (Praha) 30:251-258. Powell, P. C , B. M. Mustill, and M. Rennie, 1983. The role of histocompatibility antigens in cell-mediated cytotoxicity against Marek's disease tumour-derived lymphoblastoid cell lines. Avian Pathol. 12:461—468. Powell, P. C , K. Hala, and G. Wick, 1987. Aberrant expression of B-L (la-like) antigens on tumour cells of regressing but not of progressing Rous sarcomas. In: Avian Immunology II. W. T. Weber and D. L. Ewert, ed. Alan R. Liss, Inc., New York, NY. (in press). Rous, P., 1910. A transmissible avian neoplasm. (Sarcoma of the common fowl). J. Exp. Med. 12:696-705. Schat, K. A., W. R. Shek, B. W. Calnek, andH. Abplanalp, 1982. Syngeneic and allogeneic cell-mediated cytotoxicity against Marek's disease lymphoblastoid tumor cell lines. Int. J. Cancer 29:187-194. Schierman, L. W., 1984. Transplantable Marek's disease lymphomas. II. Variable tumor immunity induced by different lymphoblastoid cells. J. Natl. Cancer Inst. 73:423-428. Schierman, L. W., 1985. Studies on tumor immunity induced by Marek's disease lymphoblastoid cells. Pages 295-305 in: Int. Symp. Marek's Disease. B. W. Calnek and J. L. Spencer, ed. Am. Assoc, of Avian Pathol., Kennett Square, PA. Schierman, L. W., D. H. Watanabe, and R. A. McBride, 1977. Genetic control of Rous sarcoma regression in chickens: linkage with the major histocompatibility complex. Immunogenetics 5:325-332. Tseng, C. K., O. J. Fletcher, and L. W. Schierman, 1986. Preferential protection against Marek's disease virusinduced pathogenesis by immunisation with syngeneic virus-nonproducer lymphoblastoid cells. Avian
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2(Suppl. 1):38. (Abstr.) Collins, W. M., W. E. Briles, A. C. Corbett, K. K. Clark, R. M. Zsigray, and W. R. Dunlop, 1979. B locus (MHC) effect upon regression of RSV-induced tumors in noninbred chickens. Immunogenetics 9:97-100. Collins, W. M., W. E. Briles, R. M. Zsigray, W. R. Dunlop, A. C. Corbett, K. K. Clark, J. L. Marks, and T. P. McGrail, 1977. The B locus (MHC) in the chicken: association with the fate of RSV-induced tumors. Immunogenetics 5:333-343. Collins, W. M., D. W. Brown, P. H. Ward, W. R. Dunlop, and W. E. Briles, 1985. MHC and non-MHC genetic influences on Rous sarcoma metastasis in chickens. Immunogenetics 22:315-321. Collins, W. M., W. R. Dunlop, R. M. Zsigray, R. W. Briles, and R. W. Fite, 1986. Metastasis of Rous sarcoma tumors in chickens is influenced by the major histocompatibility (B) complex and sex. Poultry Sci. 65:1642-1648. Collins, W. M., E. W. Heinzelmann, A. C. Corbett, R. M. Zsigray, and W. R. Dunlop, 1980. Rous sarcoma regression in seven highly inbred lines of White Leghorns. Poultry Sci. 59:1172-1177. Collins, W. M., andR. M. Zsigray, 1984. Genetics of the response to Rous sarcoma virus-induced tumours in chickens. Anim. Blood Groups Biochem. Genet. 15:159-171. Crittenden, L. B., 1975. Two levels of genetic resistance to lymphoid leukosis. Avian Dis. 19:281-292. Cutting, J. A., D. H. Watanabe, F. R. Strebel, and R. A. McBride, 1981a. Complementing MHC- and nonMHC-linked genes and resistance to avian sarcoma virus-induced tumours in inbred lines of chickens. J. Immunogenet. 8:215-223. Cutting, J. A., D. H. Watanabe, F. R. Strebel, P. K. Vogt, and R. A. McBride, 1981b. Heterologous tumour growth patterns induced in related MHC-defined chicken lines by separate isolates of an avian sarcoma virus strain. J. Immunogenet. 8:297-305. Doherty, P. C , B. B. Knowles, and P. J. Wettstein, 1984. Immunological surveillance of tumors in the context of major histocompatibility complex restriction of T cell function. Adv. Cancer Res. 42:1-65. Doherty, P. C , and R. M. Zinkernagel, 1975. Enhanced immunological surveillance in mice heterozygous at the H-2 gene complex. Nature 256:50-52. Gebriel, G. M., and A. W. Nordskog, 1983. Influence of B complex versus non B genetic background on cellular resistance and on Rous sarcoma virus-induced tumour regression in chickens. Avian Pathol. 12:303-320. Gebriel, G. M., I. Y. Pevzner, and A. W. Nordskog, 1979. Genetic linkage between immune response to GAT and the fate of RSV-induced tumors in chickens. Immunogenetics 9:327-334. Gilmour, D. G., W. M. Collins, T. L. Frederickson, W. E. Urban, Jr., P. F. Ward, andN. L. DiFronzo. 1986. Genetic interaction between non-MHC T- and B-cell alloantigens in response to Rous sarcomas in chickens. Immunogenetics 23:1-6. Guimezanes, A., J.-L. Davignon, and A.-M. Schmitt-Verhulst, 1982. Multiple cytolytic T-cell clones with distinct cross-reactivity patterns coexist in anti-self + hapten cell lines. Immunogenetics 16:37—46. Gyles, N. R., and C. J. Brown, 1971. Selection in chickens for retrogression of tumors caused by Rous sarcoma virus. Poultry Sci. 50:901-905. Hanson, M. P., J. N. Van Zandt, and G.R.J. Law, 1967.
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