Yurochko A D, Burger C J, Elgert K D
Department of Biology, Microbiology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0406.
Cell Immunol. 1990 Apr 15;127(1):105-19. doi: 10.1016/0008-8749(90)90118-b.
The autologous mixed lymphocyte reaction (AMLR) is an in vitro measure of autoreactivity, a key mechanism in immune homeostasis. In this system, macrophages (M phi) act as accessory cells to autoreactive L3T4+ T cells by presenting self-Ia and releasing soluble modulators. During tumor growth, changes occur in M phi and T cells. Tumor-bearing host (TBH) M phi have a reduced ability to act as accessory cells. In fact, TBH M phi suppressed autoreactivity by 60-70%. The decrease in TBH M phi or T-cell abilities was not due to differences in cell numbers or incubation time. Because tumor growth causes increased prostaglandin E2 (PGE2) production by M phi, indomethacin was used to assess the contribution of prostaglandins. Normal and TBH T-cell reactivity increased nearly 50% when stimulated by normal host M phi, while normal and TBH T-cell reactivity increased nearly 100% when stimulated by TBH M phi. Thus increased prostaglandin production is partly responsible for the increased TBH suppressor M phi activity and in the normal host, suppressor M phi may be responsible for maintaining immune regulation. To assess the direct role of prostaglandins in T-cell hyporesponsiveness, PGE2 was titrated into the cultures. PGE2 suppressed normal and TBH T-cell responsiveness in a dose-dependent manner. Normal host T cells were suppressed to a greater extent than TBH T cells by PGE2 (66% versus 42% suppression, respectively). Reduced Ia expression and active suppressor mechanisms are not the only mechanisms mediating hypoautoreactivity during tumor growth. TBH autoreactive L3T4+ T cells were less responsive to self-Ia; they were only 60-80% as reactive as their normal counterparts. To address whether the helper T (TH)-cell defect involved cytokines, T cells were treated with interleukin (IL)-1, IL-2, and IL-4. In all cases, the TBH T-cell response to the factors was decreased (only 60-75% as reactive as normal T cells). Because TBH M phi-mediated suppression can override the addition of IL-1, IL-2, and IL-4, indomethacin was also added with the exogenous interleukins. This coaddition significantly enhanced normal host autoreactivity above control levels while TBH autoreactivity (the combination of TBH T cells and TBH M phi) only returned to normal host unstimulated levels. Tumor growth modulates the immune response at least by (i) decreasing the accessory cell abilities of TBH M phi through decreased Ia expression and increased production of suppressive molecules such as prostaglandins; and (ii) decreasing the responsiveness to immune enhancing factors by TH cells.
自体混合淋巴细胞反应（AMLR）是一种体外检测自身反应性的方法，自身反应性是免疫稳态的关键机制。在这个系统中，巨噬细胞（M phi）通过呈递自身Ia并释放可溶性调节剂，作为自身反应性L3T4 + T细胞的辅助细胞。在肿瘤生长过程中，M phi和T细胞会发生变化。荷瘤宿主（TBH）的M phi作为辅助细胞的能力降低。事实上，TBH的M phi将自身反应性抑制了60 - 70%。TBH的M phi或T细胞能力的下降并非由于细胞数量或孵育时间的差异。由于肿瘤生长导致M phi产生的前列腺素E2（PGE2）增加，因此使用吲哚美辛来评估前列腺素的作用。当受到正常宿主M phi刺激时，正常和TBH的T细胞反应性增加近50%，而当受到TBH的M phi刺激时，正常和TBH的T细胞反应性增加近100%。因此，前列腺素产生增加部分导致了TBH抑制性M phi活性的增加，在正常宿主中，抑制性M phi可能负责维持免疫调节。为了评估前列腺素在T细胞低反应性中的直接作用，将PGE2滴定到培养物中。PGE2以剂量依赖性方式抑制正常和TBH的T细胞反应性。PGE2对正常宿主T细胞的抑制程度大于TBH的T细胞（分别为66%和42%的抑制率）。Ia表达降低和活性抑制机制并不是肿瘤生长过程中介导低自身反应性的唯一机制。TBH自身反应性L3T4 + T细胞对自身Ia的反应性较低；它们的反应性仅为正常对应细胞的60 - 80%。为了研究辅助性T（TH）细胞缺陷是否涉及细胞因子，用白细胞介素（IL）-1、IL-2和IL-4处理T细胞。在所有情况下，TBH的T细胞对这些因子的反应均降低（仅为正常T细胞反应性的60 - 75%）。由于TBH的M phi介导的抑制可以抵消IL-1、IL-2和IL-4的添加作用，因此在添加外源性白细胞介素时也加入了吲哚美辛。这种共同添加显著增强了正常宿主的自身反应性，使其高于对照水平，而TBH的自身反应性（TBH的T细胞和TBH的M phi的组合）仅恢复到正常宿主未受刺激的水平。肿瘤生长至少通过以下方式调节免疫反应：（i）通过降低Ia表达和增加抑制性分子如前列腺素的产生，降低TBH的M phi作为辅助细胞的能力；（ii）降低TH细胞对免疫增强因子的反应性。
