MHC Loci in the Control of Marek's Lymphoma

描述（由申请人提供）：致瘤性疱疹病毒驱动大多数与HIV感染和其他免疫抑制疾病相关的癌症。在这些癌症中，免疫和肿瘤生长之间的密切联系是显而易见的。免疫抑制的解除可以带来癌症的缓解。随着时间的推移，致癌病毒、肿瘤和脊椎动物宿主之间复杂的相互作用已经进化出来。鸡的马立克病（MD）病毒为进一步了解脊椎动物遗传学在控制疱疹病毒转化引起的肿瘤生长中的作用提供了有用的模型。鸡特定的主要组织相容性复合体（MHC）单倍型在抑制MD淋巴瘤的生长中具有显著的强作用，而其他MHC单倍型只提供中等或没有保护。两种表面上相同的重组MHC单倍型在早期研究中显示对MD肿瘤的反应不同。在初步工作中，我们已经证明，尽管在I类、II类和一组BG基因座上相同，但这两种重组单倍型在一个独特的BG基因座附近的限制区域内的交叉断点不同，该基因座具有有趣的特征，可能与信号传导有关。除了不寻常的BG位点外，还有一个假定的nk细胞受体基因在控制肿瘤生长中起重要作用（被长反向重复序列包围，这些重复序列是典型的DNA易不稳定和邻近区域同源重组增加的特征）。我们寻求1)确认两种重组单倍型BR2和BR4对MD病毒攻击的反应差异，并将测试扩展到包括第三种密切相关的重组单倍型BR3，使用目前在其他MDV攻击试验中可用的完全同源菌株；2)通过重新测序交叉断点周围的间隔，确定BR2-BR4重组单倍型和MD肿瘤高抗性和高易感性单倍型候选位点上的等位基因差异；3)研究与MDV感染相关的器官候选基因座的组成表达，以及这些和其他基因座在病毒感染和肿瘤形成过程中发生的谱变化，这些基因座具有不同的MHC单倍型，感染后肿瘤生长不同。

DESCRIPTION (provided by applicant): Oncogenic herpes viruses drive most cancers associated with HIV infection and other immunosuppressed conditions. The close association between immunity and tumor growth in these cancers is obvious. Relief of immunosuppression can bring cancer remission. Over time complex interactions have evolved between oncogenic virus, tumor and vertebrate host. The Marek's disease (MD) virus in the chicken provides useful model for learning more about the role of vertebrate genetics in controlling tumor growth caused by herpes virus transformation. Particular major histocompatibility complex (MHC) haplotypes in the chicken have strikingly strong roles in suppressing the growth of MD lymphomas, while other MHC haplotypes provide moderate or no protection. Two ostensibly identical recombinant MHC haplotypes were shown in earlier studies to differ in response to MD tumors. In preliminary work we have demonstrated that, although identical at class I, class II and a cluster of BG loci, the two recombinant haplotypes differ in crossover breakpoints within a restricted region in the vicinity of a distinctive BG locus that has intriguing features and is likely involved in signaling. In addition to the unusual BG locus there is a putative NK-cell receptor gene posited as important in controlling tumor growth (surrounded by long-inverted repeats that are typical of DNA predisposed to instability and increased homologous recombination in adjacent regions). We seek to 1) confirm the difference between the two recombinant haplotypes, BR2 and BR4 in response to challenge with MD virus and extend the test to include a third closely related recombinant haplotype BR3 using fully congenic strains now available in additional MDV challenge trials; 2) define the allelic differences at the candidate loci in BR2-BR4 recombinant haplotypes and haplotypes conferring high resistance and high susceptibility to MD tumors by resequencing the interval surrounding the crossover breakpoints; and 3) study the constitutive expression of candidate loci in organs associated with MDV infection and profile changes which occur in these and other loci during the course of viral infection and tumor formation in birds that bear the different MHC haplotypes and differ in tumor growth following infection.