Ntageous to generate FGL2overexpressing Treg because fewer of these cells would be needed to achieve a clinical effect. NS-018 site Although a short course of rFGL2 did not induce tolerance in our murine transplant models, rFGL2 may have an important therapeutic role in transplant medicine and in patients with autoimmune disease. As described above, we have generated purified rFGL2 that can prevent rejection of both skin and heart allografts in mice. In transplantation, rFGL2 may have a role as an induction agent in the immediate post-transplant setting. Our in vivo studies have revealed that rFGL2 treatment is not nephrotoxic and could therefore be used to prevent rejection and allow for renal recovery following solid organ transplantation. The rFGL2 would be preferable to other agents in that it is a recombinant product and would be expected to have less batchto-batch variability than other induction agents such as thymoglobulin. Recombinant FGL2 may also have an important role in treating antibodymediated rejection, where there is a need for new therapeutic agents that target antibody production. Recombinant FGL2 would be expected to have overlapping effects with intravenous immunoglobulin (IVIG) as they both have been shown to act through FcRIIB, but rFGL2 would have the advantage of being a recombinant product and not generated from pooled human serum. Given the relatively large size of rFGL2 in its oligomeric form, we are now developing monomeric rFGL2 as a12 July 2015 Volume 6 Issue 3 eTreg and FGL2 in Alloimmunity and Autoimmunity therapeutic agent. We have already order Sulfatinib demonstrated that monomeric rFGL2 is more efficacious than oligomeric rFGL2 in inhibiting immune responses in vitro and are now testing its immunomodulatory properties in vivo.30 Blocking the FGL2 cRIIB pathway with therapeutics may provide a novel treatment for chronic viral infections and cancer. The ability to evade immune monitoring and control is now considered an important functional hallmark of cancer.92,93 The CD4+CD25+Foxp3+ Treg are observed in several tumors and play a vital role in immune suppression of effector T cells.94 Hence, it can be posited that monoclonal antibodies against FGL2 may hinder Treg-mediated immune suppression in cancer. Moreover, current dendritic cell-based cancer vaccines are promising but fail to produce long-term anti-tumor immune response.95 Therefore, as previously demonstrated, the role of FGL2 in preventing DC maturation warrants the use of anti-FGL2 mAb as potential adjuvants for DC-based vaccines for various cancers. Finally, the role of FGL2 in many cancers has not yet been studied. Gene expression analyses of human tumor samples will be necessary to identify cancers where FGL2 is overexpressed and is inhibiting host anti-cancer immunity. In addition to cancer therapy, therapeutics targeting FGL2 may also prove useful in treatment of infectious disease. Our previous studies demonstrated improved DC maturation and T cell responses to LCMV WE in fgl2-/- mice versus wildtype infected mice.76 In addition to viral disease, targeted deletion of FGL2 also demonstrated improved outcomes in mice infected with Echinococcus multilocularis, a metacestode that causes alveolar echinococcis in humans and mice.96 Using mice provided by our laboratory, the authors were able to demonstrate reduced parasite loads and increased T cell responses in fgl2-/- mice. Thus, antiFGL2 mAb may prove to be useful in treatment ofFigure 5. Potential Therapeutics Tar.Ntageous to generate FGL2overexpressing Treg because fewer of these cells would be needed to achieve a clinical effect. Although a short course of rFGL2 did not induce tolerance in our murine transplant models, rFGL2 may have an important therapeutic role in transplant medicine and in patients with autoimmune disease. As described above, we have generated purified rFGL2 that can prevent rejection of both skin and heart allografts in mice. In transplantation, rFGL2 may have a role as an induction agent in the immediate post-transplant setting. Our in vivo studies have revealed that rFGL2 treatment is not nephrotoxic and could therefore be used to prevent rejection and allow for renal recovery following solid organ transplantation. The rFGL2 would be preferable to other agents in that it is a recombinant product and would be expected to have less batchto-batch variability than other induction agents such as thymoglobulin. Recombinant FGL2 may also have an important role in treating antibodymediated rejection, where there is a need for new therapeutic agents that target antibody production. Recombinant FGL2 would be expected to have overlapping effects with intravenous immunoglobulin (IVIG) as they both have been shown to act through FcRIIB, but rFGL2 would have the advantage of being a recombinant product and not generated from pooled human serum. Given the relatively large size of rFGL2 in its oligomeric form, we are now developing monomeric rFGL2 as a12 July 2015 Volume 6 Issue 3 eTreg and FGL2 in Alloimmunity and Autoimmunity therapeutic agent. We have already demonstrated that monomeric rFGL2 is more efficacious than oligomeric rFGL2 in inhibiting immune responses in vitro and are now testing its immunomodulatory properties in vivo.30 Blocking the FGL2 cRIIB pathway with therapeutics may provide a novel treatment for chronic viral infections and cancer. The ability to evade immune monitoring and control is now considered an important functional hallmark of cancer.92,93 The CD4+CD25+Foxp3+ Treg are observed in several tumors and play a vital role in immune suppression of effector T cells.94 Hence, it can be posited that monoclonal antibodies against FGL2 may hinder Treg-mediated immune suppression in cancer. Moreover, current dendritic cell-based cancer vaccines are promising but fail to produce long-term anti-tumor immune response.95 Therefore, as previously demonstrated, the role of FGL2 in preventing DC maturation warrants the use of anti-FGL2 mAb as potential adjuvants for DC-based vaccines for various cancers. Finally, the role of FGL2 in many cancers has not yet been studied. Gene expression analyses of human tumor samples will be necessary to identify cancers where FGL2 is overexpressed and is inhibiting host anti-cancer immunity. In addition to cancer therapy, therapeutics targeting FGL2 may also prove useful in treatment of infectious disease. Our previous studies demonstrated improved DC maturation and T cell responses to LCMV WE in fgl2-/- mice versus wildtype infected mice.76 In addition to viral disease, targeted deletion of FGL2 also demonstrated improved outcomes in mice infected with Echinococcus multilocularis, a metacestode that causes alveolar echinococcis in humans and mice.96 Using mice provided by our laboratory, the authors were able to demonstrate reduced parasite loads and increased T cell responses in fgl2-/- mice. Thus, antiFGL2 mAb may prove to be useful in treatment ofFigure 5. Potential Therapeutics Tar.
