MHC Loci in the Control of Marek's Lymphoma

描述(由申请人提供)：致癌疱疹病毒导致大多数癌症与艾滋病毒感染和其他免疫抑制情况有关。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。解除免疫抑制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的复杂相互作用已经演变。鸡的马立克氏病(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。鸡中特定的主要组织相容性复合体(MHC)单倍型在抑制MD淋巴瘤的生长方面具有惊人的强大作用，而其他MHC单倍型则提供中等或没有保护作用。在早期的研究中，两种表面上相同的重组MHC单倍型被证明对MD肿瘤的反应不同。在初步工作中，我们已经证明，尽管这两种重组单倍型在I类、II类和一组BG基因座上相同，但在一个独特的BG基因座附近的限制性区域内，这两种重组单倍型的交叉断点不同，该BG基因座具有有趣的特征，并可能参与信号传递。除了不寻常的BG基因座，还有一种假定的NK细胞受体基因被认为是控制肿瘤生长的重要因素(周围环绕着长反向重复序列，这些重复序列是典型的DNA易于不稳定和邻近区域同源重组增加的典型特征)。我们试图1)确认两种重组单倍型BR2和BR4在对MD病毒攻击的反应中的差异，并扩大测试范围以包括第三个密切相关的重组单倍型BR3，使用目前在额外的MDV攻击试验中可用的完全相同的菌株；2)通过重新排序交叉断点周围的间隔来确定BR2-BR4重组单倍型和涉及MD肿瘤的高抗性和高易感性单倍型候选基因的等位基因差异；3)研究不同MHC单倍型和感染后肿瘤生长不同的禽类在与MDV感染相关的器官中的组成性表达，以及这些和其他基因座在病毒感染和肿瘤形成过程中的轮廓变化。

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.