CELL INTERACTIONS IN THREE DIMENSIONAL TISSUE CULTURE

组织中复杂的细胞-细胞相互作用是基础 因为他们的正常和病态行为。艾滋病病毒感染 淋巴组织会导致这些相互作用的恶化，并 免疫缺陷的发展。后者通常放在前面 人类免疫缺陷病毒由嗜巨噬细胞(M)表型转变 (在感染过程早期显性)对T细胞(T)嗜性。 无论是免疫缺陷的机制，还是其原因 与嗜T病毒的出现的关系是完全理解的。至 阐明人类免疫缺陷病毒感染的免疫发病机制 在体外受控条件下的人体组织，我们 正在使用我们的人类扁桃体组织培养块系统。 当在体外用Recall抗原攻击时，培养的 组织通过产生特定的抗体来做出反应。离体 人类淋巴组织感染实验室菌株和 HIV-1的初级分离株对这种免疫反应的调节作用 隔离依赖方式：T嗜性HIV-1变种显著 抑制组织免疫反应，而M嗜性艾滋病毒变异株 增强对召回抗原的免疫反应。已开发的 体液免疫缺陷是由B细胞缺陷引起的 而不是细胞外因子的缺乏。B的减值 细胞发生在感染艾滋病毒的淋巴组织的背景下， 可能是由于电池-电池接触有缺陷，或者是短程 限制在组织中的可溶性因子。M向的复制，但是 淋巴组织中T嗜性HIV-1的非特异性被抑制 外源性CC趋化因子MIP-1a或MIP-1b。感染性疾病 淋巴组织体外具有T嗜性，但不具有M嗜性HIV-1 分离株上调内源性MIP-1a和MIP-1b的表达。因此，病毒 嗜性是儿童体液免疫缺陷的决定因素 体外培养的HIV感染组织。由于两个上调的CC 趋化因子对M嗜性细胞有抑制作用，但对T嗜性细胞无关紧要 HIV变种，MIP-1a和MIP-1b的诱导可能起作用 HIV感染者的病毒嗜性从M向T的转变。 培养完整的人淋巴组织块的系统可以 有利于指导连铸组合体的发展 趋化因子或CC趋化因子为主的药物与其他抗病毒药物联合治疗 临床应用。

Complex cell-cell interactions in tissues are the basis for their normal and pathological behavior. HIV infection of lymphoid tissue leads to deterioration of these interactions and to development of immunodeficiency. The latter is often is preceded by the shift of HIV phenotype from macrophage (M)-tropic (dominant early in the course of infection) to T cell (T)-tropic. Neither the mechanisms of immunodeficiency, nor its causative relation to the emergence of T-tropic virus is fully understood. To elucidate the immunopathogenetic mechanisms of HIV infection in the context of human tissue under controlled conditions in vitro, we are using our system of histocultured blocks of human tonsils. When challenged in vitro with recall antigens, blocks of cultured tissue respond by production of specific antibodies. In vitro infection of human lymphoid tissue with laboratory strains and primary isolates of HIV-1 dysregulates this immune response in an isolate-dependent manner: T-tropic HIV-1 variants dramatically suppress the tissue immune response, while M-tropic HIV variants enhance the immune response to recall antigen. The developed humoral immunodeficiency is caused by the defects in B cells rather than by the deficiency in extracellular factors. The impairment of B cells takes place in the context of HIV-infected lymphoid tissue, probably due to the defective cell-cell contacts, or short-range soluble factors confined to the tissues. Replication of M-tropic, but not of T-tropic HIV-1 in lymphoid tissue was inhibited by exogenous CC chemokines MIP-1a or MIP-1b. Infection of lymphoid tissue in vitro with T-tropic, but not with M-tropic HIV-1 isolate upregulated endogenous MIP-1a and MIP-1b. Thus, viral tropism is the determinant of humoral immunodeficiency in HIV-infected tissues in vitro. Since both the upregulated CC chemokines are inhibitory for M-tropic but indifferent for T-tropic HIV variants, the induction of MIP-1a and MIP-1b may contribute to the shift of viral tropism from M to T in HIV-infected patients. The system of cultured blocks of intact human lymphoid tissue may be useful for guiding the development of combinations of CC chemokines or CC chemokine-based drugs with other antivirals for clinical application.