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The intricate etiology of type 1 diabetes mellitus (T1D), characterized by harmful interactions between the immune system and insulin-producing beta cells, has hindered the development of effective therapies including human islet transplantation, which requires strong immunosuppressants that impair beta cell survival and function. As such alternative immunomodulating therapies are required for successful transplantation. The discovery that pharmacological activation of the nuclear receptor LRH-1/NR5A2 can reverse hyperglycemia inmousemodels of T1D by altering, and not suppressing the autoimmune attack, prompted us to investigate whether LRH-1/NR5A2 activation could improve human islet function/survival after xenotransplantation in immunocompetent mice. Human islets were transplanted under the kidney capsule of streptozotocin (STZ)-induced diabetic mice, and treatment with BL001 (LRH-1/NR5A2 agonist) or vehicle was administered one week post-transplant. Our study, encompassing 3 independent experiments with 3 different islet donors, revealed that mice treated for 8 weeks with BL001 exhibited lower blood glucose levels correlating with improved mouse survival rates as compared to vehicle-treated controls. Human C-peptide was detectable in BL001-treated mice at both 4 and 8 weeks indicating functional islet beta cells. Accordingly, in mice treated with BL001 for 8 weeks, the beta cell mass was preserved, while a significant decrease in alpha cells was observed compared to mice treatedwith BL001 for only 4 weeks. In contrast, vehicle-treated mice exhibited a reduction in insulin-expressing cells at 8 weeks compared to those at 4 weeks. These results suggest that BL001 significantly enhances the survival, engraftment, and functionality of human islets in a STZ-induced diabetic mouse model. [ABSTRACT FROM AUTHOR]

The intricate etiology of type 1 diabetes mellitus (T1D), characterized by harmful interactions between the immune system and insulin-producing beta cells, has hindered the development of effective therapies including human islet transplantation, which requires strong immunosuppressants that impair beta cell survival and function. As such alternative immunomodulating therapies are required for successful transplantation. The discovery that pharmacological activation of the nuclear receptor LRH-1/NR5A2 can reverse hyperglycemia in mouse models of T1D by altering, and not suppressing the autoimmune attack, prompted us to investigate whether LRH-1/NR5A2 activation could improve human islet function/survival after xenotransplantation in immunocompetent mice. Human islets were transplanted under the kidney capsule of streptozotocin (STZ)-induced diabetic mice, and treatment with BL001 (LRH-1/NR5A2 agonist) or vehicle was administered one week post-transplant. Our study, encompassing 3 independent experiments with 3 different islet donors, revealed that mice treated for 8 weeks with BL001 exhibited lower blood glucose levels correlating with improved mouse survival rates as compared to vehicle-treated controls. Human C-peptide was detectable in BL001-treated mice at both 4 and 8 weeks indicating functional islet beta cells. Accordingly, in mice treated with BL001 for 8 weeks, the beta cell mass was preserved, while a significant decrease in alpha cells was observed compared to mice treated with BL001 for only 4 weeks. In contrast, vehicle-treated mice exhibited a reduction in insulin-expressing cells at 8 weeks compared to those at 4 weeks. These results suggest that BL001 significantly enhances the survival, engraftment, and functionality of human islets in a STZ-induced diabetic mouse model.

Eliminating major xenoantigens in pig cells has drastically reduced human antibody-mediated hyperacute xenograft rejection (HXR). Despite these advancements, acute xenograft rejection (AXR) remains one of the major obstacles to clinical xenotransplantation, mediated by innate immune cells, including macrophages, neutrophils, and natural killer (NK) cells. NK cells play an 'effector' role by releasing cytotoxicity granules against xenogeneic cells and an 'affecter' role on other immune cells through cytokine secretion. We highlight the key receptor-ligand interactions that determine the NK cell response to target cells, focusing on the regulation of NK cell activating receptor (NKG2D, DNAM1) and inhibitory receptor (KIR2DL1-4, NKG2A, and LIR-1) signaling pathways. Inhibition of NK cell activity may protect xenografts from cytotoxicity. Recent successful approaches to reducing NK cell-mediated HXR and AXR are reviewed, including genetic modifications of porcine xenografts aimed at improving pig-to-human compatibility. Future directions to promote xenograft acceptance are discussed, including NK cell tolerance in pregnancy and NK cell evasion in viral infection. [ABSTRACT FROM AUTHOR]

Eliminating major xenoantigens in pig cells has drastically reduced human antibody-mediated hyperacute xenograft rejection (HXR). Despite these advancements, acute xenograft rejection (AXR) remains one of the major obstacles to clinical xenotransplantation, mediated by innate immune cells, including macrophages, neutrophils, and natural killer (NK) cells. NK cells play an ‘effector’ role by releasing cytotoxicity granules against xenogeneic cells and an ‘affecter’ role on other immune cells through cytokine secretion. We highlight the key receptor-ligand interactions that determine the NK cell response to target cells, focusing on the regulation of NK cell activating receptor (NKG2D, DNAM1) and inhibitory receptor (KIR2DL1-4, NKG2A, and LIR-1) signaling pathways. Inhibition of NK cell activity may protect xenografts from cytotoxicity. Recent successful approaches to reducing NK cell-mediated HXR and AXR are reviewed, including genetic modifications of porcine xenografts aimed at improving pig-to-human compatibility. Future directions to promote xenograft acceptance are discussed, including NK cell tolerance in pregnancy and NK cell evasion in viral infection.

The recent dramatic advances in preventing "initial xenograft dysfunction" in pig-to-non-human primate heart transplantation achieved by minimizing ischemia suggests that ischemia reperfusion injury (IRI) plays an important role in cardiac xenotransplantation. Here we review the molecular, cellular, and immune mechanisms that characterize IRI and associated "primary graft dysfunction" in allotransplantation and consider how they correspond with "xeno-associated" injury mechanisms. Based on this analysis, we describe potential genetic modifications as well as novel technical strategies that may minimize IRI for heart and other organ xenografts and which could facilitate safe and effective clinical xenotransplantation. [ABSTRACT FROM AUTHOR]

The recent dramatic advances in preventing “initial xenograft dysfunction” in pig-to-non-human primate heart transplantation achieved by minimizing ischemia suggests that ischemia reperfusion injury (IRI) plays an important role in cardiac xenotransplantation. Here we review the molecular, cellular, and immune mechanisms that characterize IRI and associated “primary graft dysfunction” in allotransplantation and consider how they correspond with “xeno-associated” injury mechanisms. Based on this analysis, we describe potential genetic modifications as well as novel technical strategies that may minimize IRI for heart and other organ xenografts and which could facilitate safe and effective clinical xenotransplantation.

The current Severe Acute Respiratory Syndrome disease caused by Coronavirus-2 (SARS-CoV-2) has been a serious strain on the healthcare infrastructure mainly due to the lack of a reliable treatment option. Alternate therapies aimed at symptomatic relief are currently prescribed along with artificial ventilation to relieve distress. Traditional medicine in the form of Ayurveda has been used since ancient times as a holistic treatment option rather than targeted therapy. The practice of Ayurveda has several potent herbal alternatives for chronic cough, inflammation, and respiratory distress which are often seen in the SARS-CoV-2 infection. In this study we have used the aqueous extracts of Tinospora cordifolia (willd.) Hook. f. and Thomson in the form of Giloy Ghanvati, as a means of treatment to the SARS-CoV-2 spike-protein induced disease phenotype in a humanized zebrafish model. The introduction of spike-protein in the swim bladder transplanted with human lung epithelial cells (A549), caused an infiltration of pro-inflammatory immune cells such as granulocytes and macrophages into the swim bladder. There was also an increased systemic damage as exemplified by renal tissue damage and increased behavioral fever in the disease induction group. These features were reversed in the treatment group, fed with three different dosages of Giloy Ghanvati. The resultant changes in the disease phenotype were comparable to the group that were given the reference compound, Dexamethasone. These findings correlated well with various phyto-compounds detected in the Giloy Ghanvati and their reported roles in the viral disease phenotype amelioration. [ABSTRACT FROM AUTHOR]