上海肝病在线 Shanghai Liver Diseases' Online

HBV和HCV等病毒性肝炎相关性肝硬化采用LAK(+APC)细胞治疗依据

由于病毒感染慢性化与抗原特异性CTL和LAK活性明显低下相关，因此采用纠正低下的抗原特异性CTL和LAK活性的治疗方法有利于与慢性病毒感染慢性化防治和相关疾病发生发展，故LAK（+APC）有利于HBV、HCV等病毒感染相关性肝硬化的防治。

肝硬化的发生中，TGF-beta1是一重要的致肝纤维化因子，而VEGF和PDGF亦参与肝纤维化发生发展。TGF阻止CTL和LAK产生。因此病毒感染相关性肝硬化其抗原特异性CTL和LAK活性明显低下，故LAK（+APC）通过拮抗TGFF-beta1等免疫抑制作用而有利于HBV、HCV等病毒感染相关性肝硬化的防治。

Immunology 1989 Apr;66(4):570-6

TGF beta down-regulates TLiSA1 expression and inhibits the differentiation of precursor lymphocytes into CTL and LAK cells.

Jin B, Scott JL, Vadas MA, Burns GF.

Division of Human Immunology, Institute of Medical and Veterinary Science, Adelaide, South Australia.

This study analysed the regulatory effects of transforming growth factor beta (TGF beta) on the expression of a 70,000 MW cell surface activation antigen, TLiSA1, involved in the differentiation of cytotoxic T lymphocytes (CTL) and lymphokine-activated killer (LAK) cells from their precursor(s), and also examined the role of TGF beta in the generation of these functional cells. TGF beta was shown to suppress the expression of TLiSA1 and to inhibit, in a dose-dependent manner, the generation of both CTL and LAK cells when present from the beginning of mixed lymphocyte culture; the same inhibitory effect upon the development of cytotoxic effector cells was observed with a monoclonal antibody and with monospecific rabbit antibodies against the TLiSA1 protein. Antibody to TGF beta reversed the inhibitory effect of the cytokine on differentiation and on TLiSA1 expression. Exogenous IL-2 or, to a lesser extent, tumour necrosis factor alpha (TNF alpha) added to mixed lymphocyte cultures (MLC) augmented both TLiSA1 antigen expression and cytotoxic function by the resulting blast cells; the co-addition of TGF beta inhibited both of these cytokine-mediated effects. Similarly, it was shown that phytohaemagglutini (PHA)-induced lymphoblasts up-regulate their surface expression of TLiSA1 and exhibit increased LAK activity in response to IL-2, and TGF beta inhibited both of these events; this IL-2-induced increase in LAK cell function was also inhibited by antibodies to TLiSA1. It is suggested that TLiSA1 antigen expression is intimately linked to the differentiation of cytotoxic effector cells and that such differentiation may be a distinct process from IL-2-induced proliferation, although both events can be regulated by TGF-beta.

PMID: 2541074 TGF beta抑制LAK和CTL产生

J Immunol 1989 May 15;142(10):3452-61

IL-4 regulates IL-2 induction of lymphokine-activated killer activity from human lymphocytes.

Kawakami Y, Custer MC, Rosenberg SA, Lotze MT.

Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20892.

IL-4 is a pluripotent lymphokine acting on various cell types. We investigated the role of human IL-4 on the generation of lymphokine-activated killer (LAK) activity. Human IL-4 alone did not induce LAK activity and inhibited IL-2 induction of LAK activity from unstimulated PBMC, peripheral blood null cells, spleen cells, and lymph node cells in a dose-dependent manner. IL-4 also inhibited several phenomena induced by IL-2 such as cell proliferation, augmentation of NK activity, increase of Leu-19+ cells, and expression of IL-2R(p55) on either CD3+ or Leu-19+ cells. IL-4, however, augmented cell proliferation with other T cell mitogens including PHA, Con A, PMA, or allo-MHC Ag with or without IL-2. In contrast to unstimulated cells, IL-4 alone induced marked cell proliferation and LAK activity as well as Leu-19+ cells from in vitro IL-2 preactivated PBMC or null cells, and did not inhibit IL-2 induced cell proliferation, LAK activity, Leu-19+ cells and IL-2R(p55) expression, but rather augmented them with low doses of IL-2. Although IL-4 alone induced LAK activity from peripheral blood of some patients previously given IL-2, IL-4 inhibited in vitro LAK generation with IL-2 from these cells in most cases. Therefore, IL-4 appears to directly inhibit the IL-2 activation pathway via IL-2R(p70) and prevent resting LAK precursors from proliferating and differentiating into final effector cells. However, once cells were sufficiently preactivated by IL-2, IL-4 induced LAK activity and did not inhibit IL-2 activation of these cells. These data suggest an immunoregulatory role of IL-4 on human null cells and T cells.

PMID: 2654291 IL-4对已有的LAK有活化作用，但对静息LAK前体激活有阻止终极分化的作用

Res Commun Chem Pathol Pharmacol 1989 Jul;65(1):81-95

Suppression of lymphokine activated killer (LAK) cells by immunosuppressive substance.

Hamada F, Fuchimoto S, Orita K. First Department of Surgery, Okayama University Medical School, Japan.

We investigated the effect of immunosuppressive substance (ISS) on the immune responses mediated by interleukin 2 (IL 2). The induction of LAK cells was intensely inhibited by a high concentration of ISS (1000 micrograms/ml), but a low concentration of ISS (250-500 micrograms/ml) had no affect on the generation of LAK cells. ISS had no ability either to neutralize the activity of IL 2, or to compete with IL 2. Endogenous production of IL 2 in PHA response was not reduced by ISS, but the expression of the IL 2 receptor in the PHA response was significantly suppressed by ISS. These results suggest that ISS exerts its inhibitory effect on immune response-mediated IL 2 through modification of the IL 2 receptor.

PMID: 2789420 免疫抑制剂通过下调IL-2受体而抑制LAK活性