Halloran P F, Urmson J, Farkas S, Phillips R A, Fulop G, Cockfield S, Autenried P
Department of Medicine, University of Alberta, Edmonton, Canada.
Transplantation. 1988 Aug;46(2 Suppl):68S-72S.
The ability of lipopolysaccharide to induce major histocompatibility complex hyperexpression in vivo in a variety of mouse tissues--particularly kidney--and the effect of cyclosporine on this process were studied. MHC expression was measured by a radiolabeled antibody-binding assay using tissue homogenates, as well as by assessment of tissue sections by indirect immunoperoxidase staining. LPS administered to mice in two doses, 4 days apart, induced an increase in class I expression in several tissues but also induced an increase in class II expression in kidney. A similar increase in class II expression in kidney was not elicited with polyinosinic acid/polycytidylic acid, an agent that induces release of IFN-alpha/beta and increases class I MHC product expression. Thus we reasoned that LPS in vivo may release IFN-gamma, which then induces increased expression of MHC products. We validated this hypothesis by demonstrating that monoclonal antibody against IFN-gamma inhibited the induction of renal MHC products by LPS. However, the LPS effects did not require the participation of T cells, being demonstrable in nude mice and in mice with severe combined immunodeficiency. Moreover, the effect of LPS on MHC expression in normal and nude mice was inhibited by in vivo administration of monoclonal antibody against IFN-gamma just as it was in normal mice. Thus the class II hyperexpression that follows LPS is apparently mediated by non T cells and is due to the systemic release of IFN-gamma. This mechanism was inhibited by high doses of CsA in vivo, both in normal and in nude mice. The results indicate that there is a non T cell pathway for IFN-gamma release (and MHC induction) in vivo that is sensitive to CsA. This observation raises the possibility that some of the immunosuppressive effects of CsA may be due to inhibition of mediator release from non T cells.
研究了脂多糖在多种小鼠组织（尤其是肾脏）中体内诱导主要组织相容性复合体高表达的能力以及环孢素对这一过程的影响。通过使用组织匀浆的放射性标记抗体结合试验以及间接免疫过氧化物酶染色评估组织切片来测量MHC表达。以两种剂量、间隔4天给小鼠注射LPS，可诱导几种组织中I类表达增加，但也可诱导肾脏中II类表达增加。聚肌苷酸/聚胞苷酸（一种诱导IFN-α/β释放并增加I类MHC产物表达的试剂）未引起肾脏中II类表达的类似增加。因此我们推断，体内LPS可能释放IFN-γ，进而诱导MHC产物表达增加。我们通过证明抗IFN-γ单克隆抗体抑制LPS诱导的肾脏MHC产物来验证这一假设。然而，LPS的作用并不需要T细胞参与，在裸鼠和严重联合免疫缺陷小鼠中均可观察到。此外，与正常小鼠一样，体内注射抗IFN-γ单克隆抗体可抑制LPS对正常小鼠和裸鼠MHC表达的影响。因此，LPS后出现的II类高表达显然由非T细胞介导，且是由于IFN-γ的全身释放。在正常小鼠和裸鼠体内，高剂量的CsA均抑制了这一机制。结果表明，体内存在一条对CsA敏感的IFN-γ释放（及MHC诱导）的非T细胞途径。这一观察结果增加了CsA的一些免疫抑制作用可能是由于抑制非T细胞释放介质的可能性。
