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Ovine MHC Class II DRB1 Alleles Associated with Resistance or Susceptibility to Development of Bovine Leukemia Virus-induced Ovine Lymphoma¹

Tsukuba Life Science Center, The Institute of Physical and Chemical Research (RIKEN), Ibaraki 305-0074 [Y. N., Y. A.]; Institute for Animal Experimentation, Tohoku University School of Medicine, Sendai 980-8575 [Y. N., N. K.]; Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818 [H. K., M. O.]; and Department of Veterinary Pathology, Faculty of Agriculture, Iwate University, Morioka 020-8550 [K. O.], Japan

For the further characterization of bovine leukemia virus (BLV)-induced leukemogenesis, we investigated the association between polymorphism of ovine leukocyte antigen (OLA)-DRB1 gene and tumor development after infection of sheep with BLV. We infected 28 sheep with BLV and cloned exon 2 of the OLA-DRB1 gene from asymptomatic animals and from animals with lymphoma. Sequence analysis revealed that, among 12 healthy sheep without any evidence of tumor, ten (83.3%) carried DRB1 alleles encoding Arg-Lys (RK) at positions ß^70/71 as compared with only 6 (37.5%) of the 16 sheep with lymphoma, which suggested that alleles encoding the RK motif might protect against development of tumors after infection by BLV. By contrast, alleles encoding Ser-Arg (SR) at positions ß^70/71 were present at a significantly elevated frequency in sheep with lymphoma as compared with the healthy carriers, which indicated that OLA-DRB1 alleles encoding the SR motif might be positively related to susceptibility to tumor development. The two amino acids in these motifs line a pocket that accommodates the side chain of a bound peptide according to a model of the crystal structure of human leukocyte antigen (HLA)-DR1. To analyze immunoreactions of sheep with alleles that encoded RK or SR at ß^70/71, we selected sheep with either the RK/SR genotypes or the SR/SR genotypes and immunized them with a mixture of multiple synthetic antigenic peptides that corresponded to T-helper, T-cytotoxic, and B-cell epitopes of the BLV envelope glycoprotein gp51. Two weeks after the last immunization, all of the sheep were challenged with BLV. Sheep with the RK/SR genotype produced neutralizing antibodies against BLV; they eliminated BLV completely within 28 weeks of the BLV challenge, and they gave strong lymphocyte-proliferative responses to the peptides used for immunization. Moreover, such animals did not develop lymphoma. By contrast, sheep with the SR/SR genotype continued to produce BLV throughout the experimental period and developed terminal disease. Our results indicate that the differences in immunoresponse were due to differences in major histocompatibility complex class II alleles and reflected the risk of BLV-induced leukemogenesis. In addition, it appears that susceptibility to tumor development may be determined to some extent by polymorphic residues binding to antigenic peptides directly within the binding cleft of the OLA-DR molecule.

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