Fas Ligand as a Tool for Immunosuppression and Generation of Immune Tolerance
http://www.100md.com
《干细胞学杂志》
Department of Oncology, Immunology and Hematopoiesis Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
Key Words. Fas ligand (FasL) ? Immune privilege ? Allogeneic ? Tolerance ? gld ? lpr ? Dendritic cells
Correspondence: Curt I. Civin, M.D., Sidney Kimmel Comprehensive Cancer at Johns Hopkins, Buntin-Blaustein Cancer Research Bldg., Room 2M44, 1650 Orleans Street, Baltimore, MD 21231 USA. Telephone: 410-955-8816; Fax: 410-955-8897; e-mail: civincu@jhmi.edu
ABSTRACT
Apoptosis, or programmed cell death, is a highly regulated conserved biological pathway that is essential for the development and maintenance of cellular homeostasis . Apoptosis is crucial for the development, proper functioning, and homeostasis of the immune system . The importance of the Fas/FasL apoptotic pathway in several important functions of the immune system is demonstrated in mice with loss of function mutation of either Fas receptor (lpr mice) or FasL (gld mice) and in humans with mutated Fas (type Ia autoimmune lymphoproliferative syndrome ) or FasL (type Ib-ALPS) . Mice and humans with mutated Fas or FasL develop a phenotypically similar lymphoproliferative-autoimmune disease that is characterized by the accumulation of double-negative CD4–CD8– T lymphocytes and production of autoantibodies.
Mature peripheral T lymphocytes undergo rapid expansion after encountering antigen. To restore homeostasis and avoid autoimmunity, the majority of the antigen-stimulated activated T cells are eliminated. This process, termed "peripheral deletion," involves Fas/FasL-mediated apoptosis . In lymphoid organs, coexpression of Fas/FasL on activated T cells can lead to activation-induced cell death (AICD). In the periphery, infiltrating activated T cells induce upregulation of FasL on nonlymphoid tissues and thereby indirectly mediate their own apoptosis . Fas/FasL interactions have also been implicated in CD8+ cytotoxic T lymphocytes (CTLs) , natural killer (NK) cells , and CD4+ CTLs .
Both lpr and gld mice express high autoantibody titers. Several studies demonstrated the importance of Fas/FasL interactions in the elimination of autoreactive B cells in normal mice. Rathmell and colleagues used the hen egg lysozyme (HEL) model antigen and showed that only Fas-expressing autoreactive anti-HEL B cells were eliminated by HEL-specific CD4+ T cells. Wang and Shlomchik showed that, in Fas-deficient mice, autoreactive B cells with rheumatoid factor specificity are activated in the presence of the autoantigen, while they are ignored in normal mice. In another study, Melamed et al. demonstrated the importance of Fas in the elimination of defective B cells during development and prevention of autoimmunity.
FasL (CD95L, Apo-1L, CD178) is a type 2 conserved membrane protein of 280 amino acids (~40 kDa) that belongs to the tumor necrosis factor (TNF) family. This family also includes the death-receptor TNF, TNF-related apoptosis-inducing ligand (TRAIL/Apo-2L), and TNF weak inducer of apoptosis (TWEAK/Apo-3L) . FasL binding to its cognate receptor Fas (CD95, Apo-1) triggers the extrinsic apoptotic pathway, leading to the formation of the death-inducing signaling complex (DISC) as a consequence of recruitment of the adaptor protein FADD (Fas-associated death domain) to the Fas receptor intracellular death domain and the binding of FADD to procaspase-8 (FLICE) or -10 (FLICE-2) . Binding of procaspase-8 to FADD leads to its autocleavage and activation. Scaffidi et al. and Barnhart et al. proposed that the activation of caspase-8 could lead to cell death via two different pathways, depending on the amount of active caspase-8 that is produced at the DISC. If a high amount of activated caspase-8 is produced, which is characteristic of "type 1 cells," caspase-8 can directly initiate a caspase cascade, starting with the direct cleavage and activation of the effector procaspase-3, which then leads to cleavage of many proteins and cell death. Anti-apoptotic proteins such as Bcl-2 and Bcl-xL cannot protect type 1 cells from the death receptor–induced cell death. If a low amount of activated caspase-8 is produced, which is characteristic of "type 2 cells," Fas/FasL-mediated apoptosis relies completely on the mito-chondrial amplification loop, the intrinsic pathway, which starts with the cleavage of the pro-apoptotic Bcl-2 family member Bid by caspase-8 . Truncated Bid enters the mitochondria and initiates the release of cytochrome c and mitochondrial dysfunction by activating the pro-apoptotic Bcl-2 family members Bak and Bax . Cytochrome c triggers the formation of the cytochrome c/Apaf-1/caspase-9 complex, termed the "apoptosome," which activates caspase-9 to subsequently cleave the effector caspases, caspase-3 and caspase-7 . Fas-mediated cell death in type 2 cells can be significantly inhibited by Bcl-2 to Bcl-xL . In addition, type 2 cells taken from Bid-deficient and Bax/Bak double deficient mice are resistant to Fas-mediated cell death . The Fas/FasL apoptotic pathway is highly regulated (by regulatory mechanisms that are specific for Fas and others common to death receptors), and its abnormal regulation has been associated with cancer and autoimmunity .
Membrane FasL (mFasL) can be cleaved by matrix met-alloproteinases (MMPs) at a conserved cleavage site into a 26-kDa trimeric soluble form of FasL (sFasL), which consists of the FasL extracellular region . There is some controversy regarding the ability of sFasL to induce apoptosis. In part, this controversy might be due to the use of different forms of sFasL. To address the role of sFasL in mediating apoptosis in vivo, mice deficient in matrilysin (MMP-7), one of the MMPs that generates sFasL, were studied. These mice showed reduced Fas/FasL-mediated apoptosis of epithelial cells during prostate involution . Using supernatants of FasL-expressing cells as a source for the native sFasL, Aoki et al. showed that the cytotoxic activity of this sFasL is increased after its binding to extracellular matrix proteins. These findings led Aoki et al. to suggest that sFasL binding to extracellular matrices might be important for immune tolerance. Findings showing that the level of serum sFasL is correlated with disease progression of several malignancies and that tumor cells can evade immune surveillance by secreting sFasL to induce apoptosis of attacking T cells support the suggestion that native sFasL is active in inducing apoptosis.
Unlike Fas, which is constitutively expressed by various cell types, the tissue distribution of FasL is limited. FasL is predominantly expressed on activated T lymphocytes and NK cells . It is also expressed at immunologically privileged sites, such as the eye , brain , lung , placenta and pregnant uterus , where the inflammatory response is physiologically limited. One of the mechanisms to protect organs in immune-privileged sites is constitutive or induced expression of FasL . For instance, FasL protects the eye by mediating apoptosis of Fas+ lymphoid cells entering this organ in response to viral infection; in gld mice (with mutated FasL), the eye is not protected from inflammatory damage . This phenomenon was broadened by Hu et al. , who showed that mice with either mutated Fas or mutated FasL have a greater intensity of toxoplasma-induced intraocular inflammation than do wild-type mice.
The ability of FasL to protect tissues from immune damage is further demonstrated in corneal transplantation. Corneal transplants are the second most-used form of tissue transplant, and a high degree of graft acceptance is achieved without tissue matching. The protective role of FasL was demonstrated by showing that the constitutive expression of FasL on the cornea is important for its graft acceptance. FasL– corneas (from gld mice) were never accepted .
FasL expression has also been observed in different tumors such as colorectal carcinoma , melanoma , head and neck carcinomas , hepatocellular carcinoma , lung carcinoma , and myeloma . Studies in vitro showed that FasL+ tumor cells mediate the apoptosis of Fas-sensitive lymphoid cells . Other studies showed that melanoma cells expressing FasL had delayed tumor growth in lpr mice and that in FasL+ esophageal and colorectal tumor regions, fewer tumor-infiltrating lymphocytes but more apoptotic lymphocytes were detected, in comparison to FasL– regions of these tumors . Based on these and other findings, it has been suggested that FasL-expressing tumor cells are immune privileged and that FasL expression is one of the mechanisms used by cancer cells to evade immune surveillance. This hypothesis was challenged by studies showing that enforced over expression of FasL in FasL– tumors led to their rejection . As will be discussed later, controlled FasL expression and its coexpression with other proteins, such as transforming growth factor-beta (TGF-?), that determine the ability of FasL to mediate immune privilege, are components of strategies to achieve the benefits of FasL as a protective molecule.
The role of FasL in immune-privileged sites and its ability to protect various tumors led researchers to hypothesize that expression of FasL on allogeneic tissue transplants would protect the allograft from immune rejection. In this review, we present the findings of using FasL to reduce allograft rejection. We also present the findings of using FasL to treat different autoimmune diseases and the use of FasL-transduced dendritic cells (DCs) to achieve antigen-specific immuno-suppression and peripheral tolerance. We discuss the problems with this method and suggest ways to solve them.
FASL IN TISSUE AND ORGAN TRANSPLANTATION
Specific elimination of the autoimmune response without affecting the immune system would be an ideal treatment for autoimmune diseases. The findings that FasL mediates immune privilege and tolerance led different groups to examine the ability of FasL to abrogate autoimmune responses and to propose its use in a possible strategy for specific immunotherapy.
Hashimoto’s disease is the most common type of autoimmune thyroiditis; autoreactive CD4+ T lymphocytes initiate an autoimmune response that leads to the destruction of thyroid cells and clinical hypothyroidism . Batteux et al. examined the ability of FasL to protect the thyroid gland from autoimmune destruction in a murine model of Hashimoto’s thyroiditis that was induced by immunization with mouse thyroglobulin. The ability of transgenic mice expressing FasL on thyroid cells to prevent the induction of experimentally induced thyroiditis depended on the level of FasL expression. Mice expressing high levels of FasL showed minimal inflammatory infiltration of the thyroid, diminished autoreactive CTL and CD4+ T proliferative responses, and decreased autoantibody and Th1 cytokine production compared with control mice and mice expressing low levels of FasL.
Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the central nervous system (CNS) in which T cells reactive with proteins of the myelin sheath lead to nerve immune injury and permanent disability . Experimental autoimmune encephalomyelitis (EAE), the animal model for MS, can be induced by immunization of animals with myelin proteins such as myelin basic protein (MBP) and pro-teolipid protein (PLP) or by transferring activated T cells, specific for myelin proteins, to the host animal . Zhu et al. demonstrated the ability of FasL to prevent the development of MBP-induced EAE in Lewis rats. Rats that underwent intrathecal infusion of recombinant FasL had reduced infiltration of inflammatory cells (T cells and macrophages) into the lumbosacral spinal cord and, consistent with this, an increased percentage of apoptotic inflammatory cells compared with the control rats. This treatment did not damage the myelin sheath or neural cells in the spinal cord. In vitro, it was shown that both MBP-specific encephal-itogenic T cells and activated macrophages are sensitive to recombinant FasL-induced cell death. Systemic administration of recombinant FasL could not prevent EAE, showing that FasL acted locally within the CNS to prevent EAE. In other studies of EAE models in lpr and gld mice, Fas/FasL-mediated apoptosis has been shown to be important for the recovery from EAE .
Rheumatoid arthritis is a chronic, progressive, systemic autoimmune disease that results in inflammation and destruction of synovial joints and often erosion of the adjacent cartilage and bone, leading to substantial disability . The animal model for rheumatoid arthritis, collagen type II (CII)–induced arthritis, involves both T- and B-cell immunity to CII for disease manifestation . Zhang et al. used the CII-induced arthritis model in DBA/1 mice and showed that administration of four boosts of FasL-transduced CII-macrophages, 2 weeks after the first immunization and 2 weeks before the second immunization of the mice with CII, could significantly inhibit the development of rheumatoid arthritis, compared with the control mice treated with green fluorescent protein (GFP)–transduced CII macrophages. The treatment with FasL-transduced CII macrophages led to the elimination of CII-specific T cells, without impairment of the host immune response to other antigens such as ovalbumin (OVA). This study shows that, in order to achieve complete inhibition of development of rheumatoid arthritis, both deletion of CII-activated cells and blocking of B-cell activation are needed and that T cells have a dominant role in CII induction of rheumatoid arthritis. In another study, using lpr and gld mice, Hsu et al. demonstrated the importance of T-cell apoptosis via Fas/FasL for the ability to prevent the development of chronic arthritis subsequent to mycoplasma infection.
Autoimmune myasthenia gravis (MG) is characterized by weakness of skeletal muscles as a result of impaired neuromuscular transmission caused by antibody-mediated damage to acetylcholine receptors . Wu et al. demonstrated the ability of APCs engineered to express both acetylcholine receptor (AchR) and FasL to eliminate AchR-specific T cells. AchR-specific T cells from lpr mice were not eliminated, showing the involvement of the Fas/FasL-apoptotic pathway in T-cell depletion . Preliminary studies in vivo demonstrated the immunotherapeutic potential of this strategy for MG .
Sjogren’s syndrome (SS) is a chronic autoimmune disease that is characterized by destruction of the exocrine salivary and lacrimal glands by invading lymphocytes, especially T cells . Infection of lpr and gld mice with murine cytomegalovirus (MCMV) leads to the development of a chronic sialadenitis with severe salivary gland inflammation similar to SS . Fleck et al. used the SS model in B6-gld/gld mice and showed that local injection of the FasL gene, using the Cre/LoxP system, to the salivary glands at day 14 (acute sialadenitis) and day 75 (chronic sialadenitis) post MCMV infection led to significant reductions in the size and number of inflammatory foci, compared with the control. The treatment itself was not toxic to the gld mice.
FASL-TRANSDUCED DCS FOR INDUCTION OF PERIPHERAL TOLERANCE
Since hepatocytes constitutively express Fas, the liver is highly susceptible to Fas/FasL-mediated apoptosis, and systemic administration of FasL or anti-Fas antibody led to fulminant liver injury and lethality . One way to avoid liver toxicity, as was done in several of the studies presented in this review, is to restrict FasL expression by directing its expression to the tested tissue using a tissue-specific promoter . Another possibility is controlled FasL expression, using inducible FasL-expressing vectors such as the tetracycline-inducible expression vectors or the Cre/LoxP system . Inducible and temporal expression of FasL can also be achieved using vectors that express FasL under the control of the heat shock protein 70B promoter with ultrasound-mediated heating to turn on local FasL expression . Another possible way to mitigate the systemic effects of FasL is to block the production of sFasL by employing a noncleavable FasL mutant in which the metallo-proteinase cleavage site is deleted. Using the later strategy, the ability of the noncleavable FasL to still protect the allograft should be tested .
In the case of liver transplantation, although the liver is highly susceptible to FasL, Li et al. showed that low levels of FasL expression on allogeneic livers (~10%) are not toxic and that significant prolongation in their survival can be achieved. In contrast, when higher levels of FasL (>10%) are expressed on the allogeneic livers, lethal hepatitis developed.
Using FasL-"armed" cells to specifically delete alloreactive T cells might also nonspecifically eliminate other T cells or other cells expressing Fas receptor, especially immune cells. As was shown by Cheng et al. , transgenic mice constitutively expressing FasL in mature T cells developed normally and were healthy, and although they showed reduced T-cell numbers, they contained mature functional T cells that were resistant to Fas/FasL-mediated apoptosis. DCs, B cells, and macrophages can also resist Fas/FasL-mediated apoptosis by upregulating the expression of anti-apoptotic molecules such as c-FLIP and Bcl-xL . Also, as was mentioned above, transduction of limited numbers of cells with FasL or locally controlled FasL expression might reduce its side effects.
Aside from its ability to induce apoptosis, FasL has also pro-inflammatory characteristics and can induce the cellular release of multiple pro-inflammatory chemokines and cytokines . As was demonstrated in vivo, FasL indirectly chemo-attracts neutrophils by inducing apoptosis of Fas-expressing cells in its microenvironment . Apoptotic cells then release chemotactic factors and attract neutrophils. As was observed in several studies, overexpression of FasL on allogeneic cells and organs led to their accelerated rejection . The ability to control and regulate the opposing pro- and anti-inflammatory effects of FasL will enable enhancing FasL’s anti-inflammatory activity, block its pro-inflammatory activity, and prevent allograft rejection. Studies on immune-privileged sites have shown that constitutive expression of anti-inflammatory cytokines such as TGF-?, alpha-melanocyte-stimulating hormone (MSH) and vasoactive intestinal peptide (VIP) contributes to and complements the function of FasL . As was demonstrated by Chen et al. , the pro-inflammatory activity of FasL can be regulated by TGF-?, and in order to protect colon carcinoma cells from immune destruction, the expression of both FasL and TGF-?is needed. Therefore, one strategy to enhance the anti-inflammatory activity of FasL is to mimic its supportive microenvironment at immune-privileged sites.
As was shown on human endothelial cells, Fas/FasL-induced release of the chemokines IL-8 and monocyte chemo-attractant protein-1 (MCP-1) is triggered via a caspase-independent pathway . Other studies done in order to clarify the difference between the Fas/FasL signaling pathway leading to apoptosis and the Fas/FasL signaling pathway leading to the release of pro-inflammatory cytokines will enable the design of specific inhibitors to the Fas/FasL inflammatory pathway.
Several studies have shown that the inflammatory activity of FasL is mediated by the membrane-bound but not the soluble form of FasL . Hence, it is possible that local administration of sFasL will downregulate the pro-inflammatory activity of mFasL.
The transplantation site might also be important. As in immune-privileged sites, the microenvironment into which the cells or grafts are transplanted might support the protective role of FasL or antagonize it. As was observed by Seino et al. , FasL-transduced cells were rejected when they were transplanted subcutaneously into syngeneic mice but survived when they were transplanted under the kidney capsule. This consideration should be taken into account in transplantation of FasL-transduced DCs.
SUMMARY
The Johns Hopkins University holds patents on CD34 monoclonal antibodies and inventions related to stem cells. Dr. Civin is entitled to a share of the sales royalty received by the university under licensing agreements between the university, Becton-Dickinson Corporation, and Baxter HealthCare Corporation. Dr. Civin is a paid consultant for Becton-Dick-inson Corporation. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.
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Key Words. Fas ligand (FasL) ? Immune privilege ? Allogeneic ? Tolerance ? gld ? lpr ? Dendritic cells
Correspondence: Curt I. Civin, M.D., Sidney Kimmel Comprehensive Cancer at Johns Hopkins, Buntin-Blaustein Cancer Research Bldg., Room 2M44, 1650 Orleans Street, Baltimore, MD 21231 USA. Telephone: 410-955-8816; Fax: 410-955-8897; e-mail: civincu@jhmi.edu
ABSTRACT
Apoptosis, or programmed cell death, is a highly regulated conserved biological pathway that is essential for the development and maintenance of cellular homeostasis . Apoptosis is crucial for the development, proper functioning, and homeostasis of the immune system . The importance of the Fas/FasL apoptotic pathway in several important functions of the immune system is demonstrated in mice with loss of function mutation of either Fas receptor (lpr mice) or FasL (gld mice) and in humans with mutated Fas (type Ia autoimmune lymphoproliferative syndrome ) or FasL (type Ib-ALPS) . Mice and humans with mutated Fas or FasL develop a phenotypically similar lymphoproliferative-autoimmune disease that is characterized by the accumulation of double-negative CD4–CD8– T lymphocytes and production of autoantibodies.
Mature peripheral T lymphocytes undergo rapid expansion after encountering antigen. To restore homeostasis and avoid autoimmunity, the majority of the antigen-stimulated activated T cells are eliminated. This process, termed "peripheral deletion," involves Fas/FasL-mediated apoptosis . In lymphoid organs, coexpression of Fas/FasL on activated T cells can lead to activation-induced cell death (AICD). In the periphery, infiltrating activated T cells induce upregulation of FasL on nonlymphoid tissues and thereby indirectly mediate their own apoptosis . Fas/FasL interactions have also been implicated in CD8+ cytotoxic T lymphocytes (CTLs) , natural killer (NK) cells , and CD4+ CTLs .
Both lpr and gld mice express high autoantibody titers. Several studies demonstrated the importance of Fas/FasL interactions in the elimination of autoreactive B cells in normal mice. Rathmell and colleagues used the hen egg lysozyme (HEL) model antigen and showed that only Fas-expressing autoreactive anti-HEL B cells were eliminated by HEL-specific CD4+ T cells. Wang and Shlomchik showed that, in Fas-deficient mice, autoreactive B cells with rheumatoid factor specificity are activated in the presence of the autoantigen, while they are ignored in normal mice. In another study, Melamed et al. demonstrated the importance of Fas in the elimination of defective B cells during development and prevention of autoimmunity.
FasL (CD95L, Apo-1L, CD178) is a type 2 conserved membrane protein of 280 amino acids (~40 kDa) that belongs to the tumor necrosis factor (TNF) family. This family also includes the death-receptor TNF, TNF-related apoptosis-inducing ligand (TRAIL/Apo-2L), and TNF weak inducer of apoptosis (TWEAK/Apo-3L) . FasL binding to its cognate receptor Fas (CD95, Apo-1) triggers the extrinsic apoptotic pathway, leading to the formation of the death-inducing signaling complex (DISC) as a consequence of recruitment of the adaptor protein FADD (Fas-associated death domain) to the Fas receptor intracellular death domain and the binding of FADD to procaspase-8 (FLICE) or -10 (FLICE-2) . Binding of procaspase-8 to FADD leads to its autocleavage and activation. Scaffidi et al. and Barnhart et al. proposed that the activation of caspase-8 could lead to cell death via two different pathways, depending on the amount of active caspase-8 that is produced at the DISC. If a high amount of activated caspase-8 is produced, which is characteristic of "type 1 cells," caspase-8 can directly initiate a caspase cascade, starting with the direct cleavage and activation of the effector procaspase-3, which then leads to cleavage of many proteins and cell death. Anti-apoptotic proteins such as Bcl-2 and Bcl-xL cannot protect type 1 cells from the death receptor–induced cell death. If a low amount of activated caspase-8 is produced, which is characteristic of "type 2 cells," Fas/FasL-mediated apoptosis relies completely on the mito-chondrial amplification loop, the intrinsic pathway, which starts with the cleavage of the pro-apoptotic Bcl-2 family member Bid by caspase-8 . Truncated Bid enters the mitochondria and initiates the release of cytochrome c and mitochondrial dysfunction by activating the pro-apoptotic Bcl-2 family members Bak and Bax . Cytochrome c triggers the formation of the cytochrome c/Apaf-1/caspase-9 complex, termed the "apoptosome," which activates caspase-9 to subsequently cleave the effector caspases, caspase-3 and caspase-7 . Fas-mediated cell death in type 2 cells can be significantly inhibited by Bcl-2 to Bcl-xL . In addition, type 2 cells taken from Bid-deficient and Bax/Bak double deficient mice are resistant to Fas-mediated cell death . The Fas/FasL apoptotic pathway is highly regulated (by regulatory mechanisms that are specific for Fas and others common to death receptors), and its abnormal regulation has been associated with cancer and autoimmunity .
Membrane FasL (mFasL) can be cleaved by matrix met-alloproteinases (MMPs) at a conserved cleavage site into a 26-kDa trimeric soluble form of FasL (sFasL), which consists of the FasL extracellular region . There is some controversy regarding the ability of sFasL to induce apoptosis. In part, this controversy might be due to the use of different forms of sFasL. To address the role of sFasL in mediating apoptosis in vivo, mice deficient in matrilysin (MMP-7), one of the MMPs that generates sFasL, were studied. These mice showed reduced Fas/FasL-mediated apoptosis of epithelial cells during prostate involution . Using supernatants of FasL-expressing cells as a source for the native sFasL, Aoki et al. showed that the cytotoxic activity of this sFasL is increased after its binding to extracellular matrix proteins. These findings led Aoki et al. to suggest that sFasL binding to extracellular matrices might be important for immune tolerance. Findings showing that the level of serum sFasL is correlated with disease progression of several malignancies and that tumor cells can evade immune surveillance by secreting sFasL to induce apoptosis of attacking T cells support the suggestion that native sFasL is active in inducing apoptosis.
Unlike Fas, which is constitutively expressed by various cell types, the tissue distribution of FasL is limited. FasL is predominantly expressed on activated T lymphocytes and NK cells . It is also expressed at immunologically privileged sites, such as the eye , brain , lung , placenta and pregnant uterus , where the inflammatory response is physiologically limited. One of the mechanisms to protect organs in immune-privileged sites is constitutive or induced expression of FasL . For instance, FasL protects the eye by mediating apoptosis of Fas+ lymphoid cells entering this organ in response to viral infection; in gld mice (with mutated FasL), the eye is not protected from inflammatory damage . This phenomenon was broadened by Hu et al. , who showed that mice with either mutated Fas or mutated FasL have a greater intensity of toxoplasma-induced intraocular inflammation than do wild-type mice.
The ability of FasL to protect tissues from immune damage is further demonstrated in corneal transplantation. Corneal transplants are the second most-used form of tissue transplant, and a high degree of graft acceptance is achieved without tissue matching. The protective role of FasL was demonstrated by showing that the constitutive expression of FasL on the cornea is important for its graft acceptance. FasL– corneas (from gld mice) were never accepted .
FasL expression has also been observed in different tumors such as colorectal carcinoma , melanoma , head and neck carcinomas , hepatocellular carcinoma , lung carcinoma , and myeloma . Studies in vitro showed that FasL+ tumor cells mediate the apoptosis of Fas-sensitive lymphoid cells . Other studies showed that melanoma cells expressing FasL had delayed tumor growth in lpr mice and that in FasL+ esophageal and colorectal tumor regions, fewer tumor-infiltrating lymphocytes but more apoptotic lymphocytes were detected, in comparison to FasL– regions of these tumors . Based on these and other findings, it has been suggested that FasL-expressing tumor cells are immune privileged and that FasL expression is one of the mechanisms used by cancer cells to evade immune surveillance. This hypothesis was challenged by studies showing that enforced over expression of FasL in FasL– tumors led to their rejection . As will be discussed later, controlled FasL expression and its coexpression with other proteins, such as transforming growth factor-beta (TGF-?), that determine the ability of FasL to mediate immune privilege, are components of strategies to achieve the benefits of FasL as a protective molecule.
The role of FasL in immune-privileged sites and its ability to protect various tumors led researchers to hypothesize that expression of FasL on allogeneic tissue transplants would protect the allograft from immune rejection. In this review, we present the findings of using FasL to reduce allograft rejection. We also present the findings of using FasL to treat different autoimmune diseases and the use of FasL-transduced dendritic cells (DCs) to achieve antigen-specific immuno-suppression and peripheral tolerance. We discuss the problems with this method and suggest ways to solve them.
FASL IN TISSUE AND ORGAN TRANSPLANTATION
Specific elimination of the autoimmune response without affecting the immune system would be an ideal treatment for autoimmune diseases. The findings that FasL mediates immune privilege and tolerance led different groups to examine the ability of FasL to abrogate autoimmune responses and to propose its use in a possible strategy for specific immunotherapy.
Hashimoto’s disease is the most common type of autoimmune thyroiditis; autoreactive CD4+ T lymphocytes initiate an autoimmune response that leads to the destruction of thyroid cells and clinical hypothyroidism . Batteux et al. examined the ability of FasL to protect the thyroid gland from autoimmune destruction in a murine model of Hashimoto’s thyroiditis that was induced by immunization with mouse thyroglobulin. The ability of transgenic mice expressing FasL on thyroid cells to prevent the induction of experimentally induced thyroiditis depended on the level of FasL expression. Mice expressing high levels of FasL showed minimal inflammatory infiltration of the thyroid, diminished autoreactive CTL and CD4+ T proliferative responses, and decreased autoantibody and Th1 cytokine production compared with control mice and mice expressing low levels of FasL.
Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the central nervous system (CNS) in which T cells reactive with proteins of the myelin sheath lead to nerve immune injury and permanent disability . Experimental autoimmune encephalomyelitis (EAE), the animal model for MS, can be induced by immunization of animals with myelin proteins such as myelin basic protein (MBP) and pro-teolipid protein (PLP) or by transferring activated T cells, specific for myelin proteins, to the host animal . Zhu et al. demonstrated the ability of FasL to prevent the development of MBP-induced EAE in Lewis rats. Rats that underwent intrathecal infusion of recombinant FasL had reduced infiltration of inflammatory cells (T cells and macrophages) into the lumbosacral spinal cord and, consistent with this, an increased percentage of apoptotic inflammatory cells compared with the control rats. This treatment did not damage the myelin sheath or neural cells in the spinal cord. In vitro, it was shown that both MBP-specific encephal-itogenic T cells and activated macrophages are sensitive to recombinant FasL-induced cell death. Systemic administration of recombinant FasL could not prevent EAE, showing that FasL acted locally within the CNS to prevent EAE. In other studies of EAE models in lpr and gld mice, Fas/FasL-mediated apoptosis has been shown to be important for the recovery from EAE .
Rheumatoid arthritis is a chronic, progressive, systemic autoimmune disease that results in inflammation and destruction of synovial joints and often erosion of the adjacent cartilage and bone, leading to substantial disability . The animal model for rheumatoid arthritis, collagen type II (CII)–induced arthritis, involves both T- and B-cell immunity to CII for disease manifestation . Zhang et al. used the CII-induced arthritis model in DBA/1 mice and showed that administration of four boosts of FasL-transduced CII-macrophages, 2 weeks after the first immunization and 2 weeks before the second immunization of the mice with CII, could significantly inhibit the development of rheumatoid arthritis, compared with the control mice treated with green fluorescent protein (GFP)–transduced CII macrophages. The treatment with FasL-transduced CII macrophages led to the elimination of CII-specific T cells, without impairment of the host immune response to other antigens such as ovalbumin (OVA). This study shows that, in order to achieve complete inhibition of development of rheumatoid arthritis, both deletion of CII-activated cells and blocking of B-cell activation are needed and that T cells have a dominant role in CII induction of rheumatoid arthritis. In another study, using lpr and gld mice, Hsu et al. demonstrated the importance of T-cell apoptosis via Fas/FasL for the ability to prevent the development of chronic arthritis subsequent to mycoplasma infection.
Autoimmune myasthenia gravis (MG) is characterized by weakness of skeletal muscles as a result of impaired neuromuscular transmission caused by antibody-mediated damage to acetylcholine receptors . Wu et al. demonstrated the ability of APCs engineered to express both acetylcholine receptor (AchR) and FasL to eliminate AchR-specific T cells. AchR-specific T cells from lpr mice were not eliminated, showing the involvement of the Fas/FasL-apoptotic pathway in T-cell depletion . Preliminary studies in vivo demonstrated the immunotherapeutic potential of this strategy for MG .
Sjogren’s syndrome (SS) is a chronic autoimmune disease that is characterized by destruction of the exocrine salivary and lacrimal glands by invading lymphocytes, especially T cells . Infection of lpr and gld mice with murine cytomegalovirus (MCMV) leads to the development of a chronic sialadenitis with severe salivary gland inflammation similar to SS . Fleck et al. used the SS model in B6-gld/gld mice and showed that local injection of the FasL gene, using the Cre/LoxP system, to the salivary glands at day 14 (acute sialadenitis) and day 75 (chronic sialadenitis) post MCMV infection led to significant reductions in the size and number of inflammatory foci, compared with the control. The treatment itself was not toxic to the gld mice.
FASL-TRANSDUCED DCS FOR INDUCTION OF PERIPHERAL TOLERANCE
Since hepatocytes constitutively express Fas, the liver is highly susceptible to Fas/FasL-mediated apoptosis, and systemic administration of FasL or anti-Fas antibody led to fulminant liver injury and lethality . One way to avoid liver toxicity, as was done in several of the studies presented in this review, is to restrict FasL expression by directing its expression to the tested tissue using a tissue-specific promoter . Another possibility is controlled FasL expression, using inducible FasL-expressing vectors such as the tetracycline-inducible expression vectors or the Cre/LoxP system . Inducible and temporal expression of FasL can also be achieved using vectors that express FasL under the control of the heat shock protein 70B promoter with ultrasound-mediated heating to turn on local FasL expression . Another possible way to mitigate the systemic effects of FasL is to block the production of sFasL by employing a noncleavable FasL mutant in which the metallo-proteinase cleavage site is deleted. Using the later strategy, the ability of the noncleavable FasL to still protect the allograft should be tested .
In the case of liver transplantation, although the liver is highly susceptible to FasL, Li et al. showed that low levels of FasL expression on allogeneic livers (~10%) are not toxic and that significant prolongation in their survival can be achieved. In contrast, when higher levels of FasL (>10%) are expressed on the allogeneic livers, lethal hepatitis developed.
Using FasL-"armed" cells to specifically delete alloreactive T cells might also nonspecifically eliminate other T cells or other cells expressing Fas receptor, especially immune cells. As was shown by Cheng et al. , transgenic mice constitutively expressing FasL in mature T cells developed normally and were healthy, and although they showed reduced T-cell numbers, they contained mature functional T cells that were resistant to Fas/FasL-mediated apoptosis. DCs, B cells, and macrophages can also resist Fas/FasL-mediated apoptosis by upregulating the expression of anti-apoptotic molecules such as c-FLIP and Bcl-xL . Also, as was mentioned above, transduction of limited numbers of cells with FasL or locally controlled FasL expression might reduce its side effects.
Aside from its ability to induce apoptosis, FasL has also pro-inflammatory characteristics and can induce the cellular release of multiple pro-inflammatory chemokines and cytokines . As was demonstrated in vivo, FasL indirectly chemo-attracts neutrophils by inducing apoptosis of Fas-expressing cells in its microenvironment . Apoptotic cells then release chemotactic factors and attract neutrophils. As was observed in several studies, overexpression of FasL on allogeneic cells and organs led to their accelerated rejection . The ability to control and regulate the opposing pro- and anti-inflammatory effects of FasL will enable enhancing FasL’s anti-inflammatory activity, block its pro-inflammatory activity, and prevent allograft rejection. Studies on immune-privileged sites have shown that constitutive expression of anti-inflammatory cytokines such as TGF-?, alpha-melanocyte-stimulating hormone (MSH) and vasoactive intestinal peptide (VIP) contributes to and complements the function of FasL . As was demonstrated by Chen et al. , the pro-inflammatory activity of FasL can be regulated by TGF-?, and in order to protect colon carcinoma cells from immune destruction, the expression of both FasL and TGF-?is needed. Therefore, one strategy to enhance the anti-inflammatory activity of FasL is to mimic its supportive microenvironment at immune-privileged sites.
As was shown on human endothelial cells, Fas/FasL-induced release of the chemokines IL-8 and monocyte chemo-attractant protein-1 (MCP-1) is triggered via a caspase-independent pathway . Other studies done in order to clarify the difference between the Fas/FasL signaling pathway leading to apoptosis and the Fas/FasL signaling pathway leading to the release of pro-inflammatory cytokines will enable the design of specific inhibitors to the Fas/FasL inflammatory pathway.
Several studies have shown that the inflammatory activity of FasL is mediated by the membrane-bound but not the soluble form of FasL . Hence, it is possible that local administration of sFasL will downregulate the pro-inflammatory activity of mFasL.
The transplantation site might also be important. As in immune-privileged sites, the microenvironment into which the cells or grafts are transplanted might support the protective role of FasL or antagonize it. As was observed by Seino et al. , FasL-transduced cells were rejected when they were transplanted subcutaneously into syngeneic mice but survived when they were transplanted under the kidney capsule. This consideration should be taken into account in transplantation of FasL-transduced DCs.
SUMMARY
The Johns Hopkins University holds patents on CD34 monoclonal antibodies and inventions related to stem cells. Dr. Civin is entitled to a share of the sales royalty received by the university under licensing agreements between the university, Becton-Dickinson Corporation, and Baxter HealthCare Corporation. Dr. Civin is a paid consultant for Becton-Dick-inson Corporation. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.
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