The Study Of Immunosuppressive Effect Of Apoptotic Cells

Apoptosis plays an important role in differentiation, development and pathophysiological processes such as inflammation, neoplasia and autoimmune diseases. For a long time, apoptotic cells per se and the clearance of apoptotic cells had been viewed as neutral in immune response. Because of the specific recognition of molecules on the surface of apoptotic cells, the apoptotic cells always been engulfed by scavenger efficiently. This silent removal mechanism ensures the protection of neighboring cells from being damaged by the cellular content of apoptotic cells. On the contrary, cells dying by necrosis send "danger signal" to the immune system (Matzinger, 1994) and, thus, result in an immune response. Due to release TGFpi, a potent immunosuppresant, apoptotic cells could induce immune tolerance. Production of TGFpi by apoptotic cells was first found in anti-immunoglobulin-induced apoptosis in murine B-cell lymphomas. Subsequently, TGFpi was also found to be present in other cells undergoing apoptosis. For example, tamoxifen-induced apoptosis in breast cancer cells is accompanied by the production of TGFβ1.Testosterone, which induces apoptosis in thymocytes, also leads to the expression of TGFβ1. Recently many investigations suggested that apoptotic cells release latent and also active TGFpi, which contributes to the establishment of local immunosuppressive milieu. Interestingly, some investigations revealed that after apoptotic cells were bounded or ingested by macrophages, the secretion of immunosuppressive cytokines such as IL-10,TGFβI was increased markedly, whereas the secretion of pro-inflammatory cytokines such as TNFa, IL-12 and IL-1β were suppressed. These results imply that apoptotic cells or phagocytosis of apoptotic cells may actively regulate immune response. Reiter and Krammer found that necrotic tumor cells help macrophages kill tumor cells, but that, apoptotic tumor cells decrease the competence of macrophage in clearance of tumor cells, and enhance prompt the growth of tumor cells. In addition, phagocytosis of apoptotic cells was found to inhibit macrophage activity and finally stimulate the growth of Trypanosoma cruzi. After phagocytosis of necrotic cells the immature dendritic cells were actived, the expression of MHCII and costimulatory molecular were up-regulated, while phagocytosis of apoptotic cells has not such results.Many evidence showed that the liver is accountable for the induction of immune tolerance. The liver transplantation could induce tolerance to allografts, including the pancreas, small intestine and even xenografts. The majority of CD8~+ T-cells were depleted from the periphery and accumulated in the liver in apoptotic form, which result in a decline in peripheral CD8~+ T-cells. Expression of B220 on T-cells indicates that they are doomed to undergo apoptosis. In contrast to most other tissues, LPS in the liver does not evoke an inflammatory response, but down-regulates the efficiency of antigen presentation by liver sinusoidal endothelial cells. All these evidence suggested that liver tolerance is due to apoptotsis of activated T lymphocytes in the liver.These investigations strongly indicate that apoptotic cells are not "passive." On the contrary they actively participate in regulating the immune response. Necrotic cells send a "danger signal" to the immune system and thus evoke strong immune response, while cells dying by apoptosis do not send a danger signal to the immune system, and finally induce T lymphocytes to become tolerant. However, if apoptotic cells are not engulfed effectively, they will undergo secondary lysis, which could send out danger signal to the immune system and finally result in immune response. This causes immunologists to give second thought to the significance of apoptotic cells and the clearance of apoptotic cells. John Savill et al suggested that the phagocytosis of apoptoticcells should not only be viewed as clearing aging cells to make room for functional cells, but also setting up the immunosuppressive milieu at the local site. In this paper we...