While kidney transplantation (KTx) has traditionally required lifelong immunosuppression, an investigational stem cell therapy, FCR001, has been demonstrated to induce tolerance and eliminate the need for immunosuppression through the establishment of persistent mixed chimerism in a phase 2 clinical study. Real‐world evidence (RWE) methods were employed to compare the safety and efficacy of non‐myeloablative conditioning with FCR001 with standard of care [SOC] immunosuppression in a retrospective single‐center analysis of outcomes among propensity score matched living‐donor KTx receiving SOC (n = 144) or FCR001 (n = 36). Among the FCR001 recipients, 26 (72%) developed persistent chimerism allowing durable elimination of all immunosuppression. There was no significant difference in the composite primary endpoint (biopsy‐proven acute rejection [BPAR], graft loss, or death) at 60 months (FCR001 27.8%, n = 10 and SOC 28.5%, n = 41; p = .9). FCR001 recipients demonstrated superior kidney function at 5 years (estimated glomerular filtration rate [eGFR] [mean ± standard deviation]: 64.1 ± 15.3) compared to SOC (51.7 ± 18.8; p = .02). At 5 years, FCR001 recipients experienced fewer complications including new‐onset diabetes post‐transplant, although two patients developed graft versus host disease. In conclusion, RWE demonstrated that KTx combined with non‐myeloablative conditioning and FCR001 resulting in superior kidney function without increasing the risk of rejection, graft loss, or death among patients off immunosuppression.

Scleroderma is a rare, potentially fatal, clinically heterogeneous, systemic autoimmune connective tissue disorder that is characterized by progressive fibrosis of the skin and visceral organs, vasculopathy and immune dysregulation. The more severe form of the disease, diffuse cutaneous scleroderma (dcSSc), has no cure and limited treatment options. Haematopoietic stem cell transplantation has emerged as a potentially disease-modifying treatment but faces challenges such as toxicity associated with fully myeloablative conditioning and recurrence of autoimmunity. Novel cell therapies-such as mesenchymal stem cells, chimeric antigen receptor-based therapy, tolerogenic dendritic cells and facilitating cells-that may restore self-tolerance with more favourable safety and tolerability profiles are being explored for the treatment of dcSSc and other autoimmune diseases. This narrative review examines these evolving cell therapies.

Detailed knowledge regarding the nature of and mechanisms causing neutron irradiation damage in graphite remains a scientific and technological challenge, particularly at high irradiation doses. Using electrons as a surrogate for neutron irradiation, we develop a time-dependent atomistic reconstruction strategy fed by a time series of high-resolution transmission electron microscopy (HRTEM) images, to monitor damage propagation in a graphite grain up to a dose of about one displacement per atom (i.e. well beyond the conventional irradiation simulations based on molecular dynamics). The reduction in crystalline order and the development of interlayer bonding observed in the models with increasing irradiation time induce significant modifications of the elastic constants and thermal conductivity. Homogenizing these properties to the case of isotropic polycrystalline graphite we are able to reproduce the increase in Young's modulus and decrease in thermal conductivity observed experimentally for reactor graphites with increasing dose. Further validation of the models is provided via a comparison of simulated and experimental data from irradiated material such as: HRTEM images, carbon K-edge electron energy loss spectra, dose rate and stored energies.

(R,R′)-4′-Methoxy-1-naphthylfenoterol (MNF) promotes growth inhibition and apoptosis of human HepG2 hepatocarcinoma cells via cannabinoid receptor (CBR) activation. The synthetic CB1R inverse agonist, AM251, has been shown to block the anti-mitogenic effect of MNF in these cells; however, AM251 is also an agonist of the recently deorphanized, lipid-sensing receptor, GPR55, whose upregulation contributes to carcinogenesis. Here, we investigated the role of MNF in GPR55 signaling in human HepG2 and PANC-1 cancer cell lines in culture by focusing first on internalization of the fluorescent ligand Tocrifluor 1117 (T1117). Initial results indicated that cell pretreatment with GPR55 agonists, including the atypical cannabinoid O-1602 and l-α-lysophosphatidylinositol, dose-dependently reduced the rate of cellular T1117 uptake, a process that was sensitive to MNF inhibition. GPR55 internalization and signaling mediated by O-1602 was blocked by MNF in GPR55-expressing HEK293 cells. Pretreatment of HepG2 and PANC-1 cells with MNF significantly abrogated the induction of ERK1/2 phosphorylation in response to AM251 and O-1602. Moreover, MNF exerted a coordinated negative regulation of AM251 and O-1602 inducible processes, including changes in cellular morphology and cell migration using scratch wound healing assay. This study shows for the first time that MNF impairs GPR55-mediated signaling and, therefore, may have therapeutic potential in the management of cancer.

(R,R′)-4′-Methoxy-1-naphthylfenoterol (MNF) promotes growth inhibition and apoptosis of human HepG2 hepatocarcinoma cells via cannabinoid receptor (CBR) activation. The synthetic CB1R inverse agonist, AM251, has been shown to block the anti-mitogenic effect of MNF in these cells; however, AM251 is also an agonist of the recently deorphanized, lipid-sensing receptor, GPR55, whose upregulation contributes to carcinogenesis. Here, we investigated the role of MNF in GPR55 signaling in human HepG2 and PANC-1 cancer cell lines in culture by focusing first on internalization of the fluorescent ligand Tocrifluor 1117 (T1117). Initial results indicated that cell pretreatment with GPR55 agonists, including the atypical cannabinoid O-1602 and l-α-lysophosphatidylinositol, dose-dependently reduced the rate of cellular T1117 uptake, a process that was sensitive to MNF inhibition. GPR55 internalization and signaling mediated by O-1602 was blocked by MNF in GPR55-expressing HEK293 cells. Pretreatment of HepG2 and PANC-1 cells with MNF significantly abrogated the induction of ERK1/2 phosphorylation in response to AM251 and O-1602. Moreover, MNF exerted a coordinated negative regulation of AM251 and O-1602 inducible processes, including changes in cellular morphology and cell migration using scratch wound healing assay. This study shows for the first time that MNF impairs GPR55-mediated signaling and, therefore, may have therapeutic potential in the management of cancer.

Introduction We previously reported the induction of kidney transplant tolerance by the establishment of durable whole blood and T-cell chimerism and withdrawal of immunosuppression (IS) in 26 of 37 highly mismatched recipients of combined stem cell and living donor kidney transplant recipients (KTx) with low risk of graft versus host disease (GvHD), using FCR001, an investigational cell therapy. The focus of the current analysis is to evaluate the impact of degree of bidirectional donor/recipient mismatching using high resolution allele typing at HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1, on the ability to establish durable chimerism, allowing full immunosuppression (IS) withdrawal and the induction of transplant tolerance. Methods In this phase 2 trial, recipients received nonmyeloablative conditioning with fludarabine 30mg/m2 (Days -5, -4, -3), cyclophosphamide 50mg/kg (Days-3 and +3), 200 cGy TBI (Day-1) followed by KTx (Day 0). G-CSF mobilized peripheral blood mononuclear cells were apheresed from the donor >2 weeks prior to KTx, processed to remove GvHD-producing cells yet retain CD34 +cells and tolerogenic CD8+/TCR facilitating cells (FC) and cryopreserved until infusion day+1 after KTx. IS consisted of mycophenolate and tacrolimus. IS was weaned and discontinued in the presence of sustained donor T-cell chimerism (>50%), stable renal function and no evidence of biopsy-proven rejection. Results Samples from 32 of the 37 subject pairs were available for analysis; of these, three subjects did not have sufficient DNA to test for locus DPB1.All 32 recipients, ranging from age 18 - 65 years, have reached at least 4.5 years of follow-up up to 12 years. Two recipients were re-transplants. Of the 29 D/R pairs with data from all 12 alleles, 21 were mismatched between 6 to 12 alleles (6 related, 15 unrelated), 8 were mismatched between 2 and 5 alleles (all related). Of the three D/R pairs missing DP data, one was mismatched 6 of 10, another 10 of 10, and a third 2 of 10 alleles. Despite the high degree of mismatch, durable chimerism allowed for full IS withdrawal in 25 of these 32 subjects (time off IS from 3.5 - 11 years). 12/25 off IS were from unrelated D/R pairs and ≥ 8 HLA mismatches; the majority showed >95% donor whole blood/T cell chimerism. Three have exhibited stable mixed chimerism ranging between 40% - 60%. Of the subjects not off IS, two failed to engraft their cells; four lost chimerism by 4 months, and one developed GVHD. Durably chimeric patients retained chimerism after removal of IS, remain rejection-free without donor-specific antibody (DSA) with up to 12 years following KTx and have not resumed IS. Transiently chimeric subjects resumed endogenous hematopoiesis and are maintained on low dose IS with stable renal function. There have been two cases of GvHD: one grade 2 lower GI acute GvHD that developed during conversion from tacrolimus to sirolimus and responded to steroids; this patient has developed moderate chronic GvHD of the skin. He is off IS with normal renal function. The second presented late following development of severe gastrointestinal symptoms and manifested treatment-resistant lower GI GvHD with associated tissue-invasive CMV colitis that proved fatal at 11 months post-transplant. Conclusions In summary, high levels of durable chimerism and tolerance with a low (5.5%) incidence of GvHD has been achieved in highly mismatched related and unrelated recipients of FCR001 + kidney transplant. Figure 1 Figure 1. Krieger: Talaris Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Tambur: Viela Bio and Sanofi: Consultancy; ThermoFisher: Speakers Bureau. Schneider: Talaris Therapeutics, Inc.: Current Employment. Olsen: Talaris Therapeutics, Inc.: Current Employment. Ildstad: Talaris Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.