Allograft Survival Research Articles

T cell specific deletion of IRF4 with Ox40-Cre impairs effector and memory T cell responses in heart transplantation

BackgroundIRF4 is the pioneer factor for effector T cell maturation. Here we investigated the function of IRF4 in maintaining OX40-related T cell responses following alloantigen activation in a mouse heart transplantation model. MethodsIrf4flox/flox mice were bred with Ox40cre/+ mice to generate Irf4flox/floxOx40cre/+ mice. Wild type C57BL/6, Irf4flox/floxOx40cre/+ mice were transplanted with BALB/c heart allografts, with or without BALB/c skin-sensitization. CD4+ TEa T cells co-transfer experiments and flow cytometric analysis were conducted to investigate the amount of CD4+ T cells and the percentage of the T effector subset. ResultsIrf4flox/floxOx40cre/+ and Irf4flox/floxOx40cre/+ TEa mice were constructed successfully. IRF4 ablation in activated OX40-mediated alloantigen specific CD4+ TEa T cells reduced effector T cell differentiation (CD44hiCD62Llo, Ki67, IFN-γ), which caused long-term allograft survival (> 100 d) in the chronic rejection model. In the donor skin-sensitized heart transplantation model, the formation and function of alloantigen-specific memory CD4+ TEa cells were also impaired in Irf4flox/floxOx40cre/+ mice. Additionally, deletion of IRF4 after T cell activation in Irf4flox/floxOx40cre/+ mice reduced T cell reactivation in vitro. ConclusionsIRF4 ablation after OX40-related T cell activation could reduce effector and memory T cell formation and inhibit their function in response to alloantigen stimulation. These findings could have significant implications in targeting activated T cells to induce transplant tolerance.

Evolution of the technique of renoportal anastomosis for patients with complete portal venous occlusion in living donor liver transplantation - a retrospective cohort study.

This study aimed to present our surgical technique and the long-term outcomes of living donor liver transplantations with renoportal anastomosis for patients with complete portal venous occlusion. Renoportal anastomosis (RPA) is a promising technique for portal flow reconstruction during liver transplantation in patients with complete occlusion of the portal vein and extensive splanchnic vein thrombosis. However, reports demonstrating living donor liver transplantations (LDLT) with renoportal anastomosis are rarer than those demonstrating deceased-donor liver transplantation. In this single-center retrospective cohort study, we analyzed the medical records of patients who underwent portal flow reconstruction via RPA with end-to-end anastomosis between the interposition graft and LRV-connected inferior vena cava (VC) cuff. The outcomes included postoperative RPA-related morbidity and patient and allograft survival for patients who underwent LDLT with RPA. Fifteen patients underwent LDLT with portal flow reconstruction via RPA from January 2005 to December 2019. The median follow-up period was 80.7 months (range: 27d-195.2mo). RPA evolved from end-to-end anastomosis in 1 (6.7%) patient to end-to-side anastomoses in the next 6 (40%) patients and finally, to end-to-end anastomoses between the inferior VC cuff connected to the left renal vein (LRV) and interposing vascular grafts in 8 (53.3%) patients. After standardization of the RPA technique from the eighth case in 2011, the incidence rate of RPA-related complications significantly decreased from 42.9% (3/7) to 12.5% (1/8). At the last follow-up, all 11 surviving patients had normal liver function, and 10 patients had patent anastomoses on imaging examination. Our standardized RPA technique using an inferior VC cuff connected to the LRV creates a safe end-to-end RPA.

Kidney Transplantation From Donors With Acute Kidney Injury: Are the Concerns Justified? A Systematic Review and Meta-Analysis.

Renal transplantation improves quality of life and prolongs survival in patients with end-stage kidney disease, although challenges exist due to the paucity of suitable donor organs. This has been addressed by expanding the donor pool to include AKI kidneys. We aimed to establish whether transplanting such kidneys had a detrimental effect on graft outcome. The primary aim was to define early outcomes: delayed graft function (DGF) and primary non-function (PNF). The secondary aims were to define the relationship to acute rejection, allograft survival, eGFR and length of hospital stay (LOS). A systematic literature review and meta-analysis was conducted on the studies reporting the above outcomes from PubMed, Embase, and Cochrane Library databases. This analysis included 30 studies. There is a higher risk of DGF in the AKI group (OR = 2.20, p < 0.00001). There is no difference in the risk for PNF (OR 0.99, p = 0.98), acute rejection (OR 1.29, p = 0.08), eGFR decline (p = 0.05) and prolonged LOS (p = 0.11). The odds of allograft survival are similar (OR 0.95, p = 0.54). Transplanting kidneys from donors with AKI can lead to satisfactory outcomes. This is an underutilised resource which can address organ demand.

Extracorporeal photopheresis in the treatment of cardiac allograft rejection: A single-centre experience

Despite novel immunosuppressive (IS) protocols, adverse effects of IS drugs continue to have notable negative impact on patient and cardiac allograft survival after heart transplantation (HTx). Therefore, IS regimens with less toxic side effects are sorely needed. We aimed to evaluate the efficacy of extracorporeal photopheresis (ECP) in combination with tacrolimus-based maintenance IS therapy in the treatment of allograft rejection in adult HTx recipients. Indications for ECP included acute moderate-to-severe or persistent mild cellular rejection, or mixed rejection. Twenty-two patients underwent a median of 22(2–44) ECP treatments after HTx. Median duration of ECP course was 173.5(2–466) days. No relevant adverse effects of ECP were noted. Reduction of methylprednisolone doses was safe throughout the ECP course. ECP, used in conjunction with pharmacological anti-rejection therapy, had a successful reversal of cardiac allograft rejection, decreased the rates of subsequential rejection episodes and normalized the allograft function in patients completing the ECP course. Short- and long-term survivals were excellent (91% at 1 and 5 years post-ECP) and comparable to International Society for Heart and Lung Transplantation registry data on HTx recipient overall survival. In conclusion, ECP can be safely used for the treatment and prevention of cardiac allograft rejection in conjunction with traditional IS regimen.

MTOR-inhibitors and post-transplant diabetes mellitus: a link still debated in kidney transplantation.

The mammalian target of rapamycin inhibitors (mTOR-Is, Sirolimus, and Everolimus) are immunosuppressive drugs widely employed in kidney transplantation. Their main mechanism of action includes the inhibition of a serine/threonine kinase with a pivotal role in cellular metabolism and in various eukaryotic biological functions (including proteins and lipids synthesis, autophagy, cell survival, cytoskeleton organization, lipogenesis, and gluconeogenesis). Moreover, as well described, the inhibition of the mTOR pathway may also contribute to the development of the post-transplant diabetes mellitus (PTDM), a major clinical complication that may dramatically impact allograft survival (by accelerating the development of the chronic allograft damage) and increase the risk of severe systemic comorbidities. Several factors may contribute to this condition, but the reduction of the beta-cell mass, the impairment of the insulin secretion and resistance, and the induction of glucose intolerance may play a pivotal role. However, although the results of several in vitro and in animal models, the real impact of mTOR-Is on PTDM is still debated and the entire biological machinery is poorly recognized. Therefore, to better elucidate the impact of the mTOR-Is on the risk of PTDM in kidney transplant recipients and to potentially uncover future research topics (particularly for the clinical translational research), we decided to review the available literature evidence regarding this important clinical association. In our opinion, based on the published reports, we cannot draw any conclusion and PTDM remains a challenge. However, also in this case, the administration of the lowest possible dose of mTOR-I should also be recommended.

Safety and Efficacy of Conversion to Once-Daily Tacrolimus from Twice-Daily Tacrolimus in Pediatric Liver Transplant Recipients

BackgroundNonadherence to immunosuppression is the most common cause of late acute rejection in pediatric liver transplant (LT) recipients. A prolonged-release once-daily tacrolimus formulation was developed to improve adherence and long-term allograft survival. MethodsWe screened 179 pediatric LT recipients who converted from twice-daily tacrolimus (TD-TAC) to once-daily tacrolimus (OD-TAC) between February 2011 and September 2019. ResultsOne hundred seventy-nine recipients converted to OD-TAC and were followed for 18 months. 152 OD-TAC-converted recipients (84.9%) experienced uneventful follow-up, while 21 recipients showed LFT elevation. Four recipients had biopsy-proven acute rejection within six months of conversion, all of which were successfully treated with steroid pulse. 166 recipients (92.7%) remain on OD-TAC and 13 (7.3%) were switched back to TD-TAC. The mean tacrolimus trough level significantly decreased three months following conversion (3.14 ± 1.9 ng/mL) compared with pre-conversion levels (3.69 ± 1.98 ng/mL). Mean tacrolimus trough levels remained unchanged from 3 months to 12 months following conversion. Percent coefficient of variation of tacrolimus trough levels decreased significantly from 32.5 ± 16.4 ng/mL to 27.5 ± 15.6 ng/mL after conversion to OD-TAC, reflecting a decrease in variation of tacrolimus trough levels following conversion. ConclusionsConversion to OD-TAC in pediatric LT recipients with stable graft function is safe and effective. Level of evidenceLevel IV.

Naringenin Impedes the Differentiation of Mouse Hematopoietic Stem Cells Derived from Bone Marrow into Mature Dendritic Cells, thereby Prolonging Allograft Survival.

The use of immature dendritic cells (imDCs) to induce donor-specific immunotolerance following in vivo stimulation is limited by their low rate of induction and their tendency to undergo maturation. We derived imDCs from bone marrow hematopoietic stem cells (HSCs-imDCs). We then tested the ability of naringenin (Nar) to impede the maturation of HSCs-imDCs for inducing transplantation immune tolerance. HSCs derived from bone marrow were collected and induced to differentiate into imDCs by treating with Nar (Nar-HSCs-imDCs). Flow cytometry was used to evaluate DC surface markers, apoptosis, and endocytic ability. The ability of DCs to influence the in vitro proliferation of T cells and of regulatory T cells (Tregs) was analyzed by mixed lymphocyte reaction assays. Enzyme-linked immunoassays were used to quantify cytokine levels in supernatants from co-cultured DCs and Tregs, as well as in the serum of experimental animals. The level of immunotolerance induced by Nar-HSCs-imDCs was evaluated by skin grafting in recipient Balb/c mice, while the Kaplan-Meier method was used to statistically evaluate graft survival. Compared with HSC-imDCs, Nar-HSCs-imDCs showed higher expression of cluster of differentiation 11c (CD11c), but lower expression levels of CD80, CD86, and major histocompatibility complex class II. Nar-HSCs-imDCs also showed stronger inhibition of T cells and higher Treg cell proliferation. Interleukin 2 (IL-2) and interferon gamma levels were downregulated in Nar-HSCs-imDCs, whereas IL-4, IL-10, and transforming growth factor beta levels were upregulated. The rate of apoptosis and endocytic capacity of Nar-HSCs-DCs increased significantly after treatment with lipopolysaccharide. HSCs-imDCs or Nar-HSCs-imDCs were injected into Balb/c mice via the tail vein 7 days before skin grafting. Significantly reduced donor-specific CD4+ T cells and induced proliferation of CD4+CD25+FoxP3+ Treg cells were observed in the spleen of mice from the Nar-HSCs-imDCs group, especially at a dose of 106 Nar-HSCs-imDCs. The latter group also showed significantly prolonged survival of skin grafts. Nar-HSCs-imDCs markedly improved the acceptance of organ allografts, offering a potentially new strategy for inducing immune tolerance in transplantation.

Outcomes after flow cytometry crossmatch-positive lung transplants managed with perioperative desensitization

Our program previously reported successful outcomes following virtual crossmatch (VXM)–positive lung transplants managed with perioperative desensitization, but our ability to stratify their immunologic risk was limited without flow cytometry crossmatch (FCXM) data before 2014. The aim of this study was to determine allograft and chronic lung allograft dysfunction (CLAD)–free survival following VXM-positive/FCXM-positive lung transplants, which are performed at a minority of programs due to the high immunologic risk and lack of data on outcomes. All first-time lung transplant recipients between January 2014 and December 2019 were divided into 3 cohorts: VXM-negative (n = 764), VXM-positive/FCXM-negative (n = 64), and VXM-positive/FCXM-positive (n = 74). Allograft and CLAD-free survival were compared using Kaplan-Meier and multivariable Cox proportional hazards models. Five-year allograft survival was 53% in the VXM-negative cohort, 64% in the VXM-positive/FCXM-negative cohort, and 57% in the VXM-positive/FCXM-positive cohort (P = .7171). Five-year CLAD-free survival was 53% in the VXM-negative cohort, 60% in the VXM-positive/FCXM-negative cohort, and 63% in the VXM-positive/FCXM-positive cohort (P = .8509). This study confirms that allograft and CLAD-free survival of patients who undergo VXM-positive/FCXM-positive lung transplants with the use of our protocol does not differ from those of other lung transplant recipients. Our protocol for VXM-positive lung transplants improves access to transplant for sensitized candidates and mitigates even high immunologic risk.

Outcomes based on induction regimens in pediatric kidney transplantation: a NAPRTCS and PHIS collaborative study.

Induction agent used at the time of kidney transplant is often based upon center practice and recipient characteristics. We evaluated outcomes across induction therapies among children enrolled in the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) transplant registry with data in the Pediatric Health Information System (PHIS). This is a retrospective study of merged data from NAPRTCS and PHIS. Participants were grouped by induction agent: interleukin-2 receptor blocker (IL-2 RB), anti-thymocyte/anti-lymphocyte globulin (ATG/ALG), and alemtuzumab. Outcomes assessed included 1-, 3-, and 5-year allograft function and survival, rejection, viral infections, malignancy, and death. A total of 830 children transplanted between 2010 and 2019. At 1year post-transplant, the alemtuzumab group had higher median eGFR (86ml/min/1.73m2) compared to IL-2 RB and ATG/ALG (79 and 75ml/min/1.73m2, respectively; P < 0.001); at 3 and 5years, there was no difference. Adjusted eGFR over time was similar across all induction agents. Rejection rates were lower among the alemtuzumab group vs. IL-2RBand ATG (13.9% vs. 27.3% and 24.6%, respectively; P = 0.006). Adjusted ATG/ALG and alemtuzumab had higher hazard ratio for time to graft failure compared to IL-2 RB (HR 2.48 and HR 2.11, respectively; P < 0.05). Incidence of malignancy, mortality, and time to first viral infection was similar. Although rejection and allograft loss rates were distinct, the incidences of viral infection and malignancy were comparable across induction agents. By 3years post-transplant, there was no difference in eGFR. A higher resolution version of the Graphical abstract is available as Supplementary information.

TIPE2 deficiency prolongs mouse heart allograft survival by facilitating immature DCs-induced Treg generation

It has been reported that deletion of tumor necrosis factor-α-induced protein-8 like 2 (TNFAIP8L2, TIPE2) facilitates the activation of T-cell receptors. However, the role of TIPE2 in T-cell-mediated acute transplant rejection remains unclear. To illustrate the underlying cellular mechanisms, we transplanted BALB/c hearts into C57BL/6 wild-type (WT) or C57BL/6 mice deficient for TIPE2 (TIPE2−/−) and found that TIPE2−/− recipient mice showed significantly prolonged survival of heart allografts and suppressed maturation of CD11c+ dendritic cells (DCs), which largely abolished the activation and proliferation of alloreactive T cells and their cytotoxic activity. TIPE2−/− DCs increased CD4+CD25+Foxp3+CD127− regulatory T cells (Tregs)generation, likely by inhibiting DCs maturation and CD80 and CD86 expression. Administration of anti-CD25 abolished the allograft survival induced by TIPE2 deficiency. Moreover, TIPE2 deficiency increased IL-10 production in T cells and in recipient serum and allografts. Mechanistic studies revealed that TIPE2−/− restrained the maturation of DCs via inhibition of PI3K/AKT phosphorylation during alloantigen stimulation. Taken together, TIPE2 deficiency in recipient mice inhibited acute rejection by increasing Tregs generated by immature DCs. Thus, TIPE2 could be a therapeutic target for suppressing rejection in organ transplantation.

Living Donor Kidney Transplant in Recipients With Glomerulonephritis: Donor Recipient Biologic Relationship and Allograft Outcomes.

Using the Scientific Registry of Transplant Recipients, we examined the association between donor-recipient biologic relationship and long-term recipient and allograft survival among glomerulonephritis (GN) patients. Four GN types were studied: membranous nephropathy, IgA, lupus-associated nephritis, and focal segmental glomerulosclerosis (FSGS). We identified all adult primary living-donor recipients between 2000 and 2018 (n = 19,668): related (n = 10,437); unrelated (n = 9,231). Kaplan-Meier curves were generated for the recipient, death-censored graft survival and death with functioning graft through ten years post-transplant. Multivariable Cox proportional hazard models were used to examine the association between the donor-recipient relationship and outcomes of interest. There was an increased risk for acute rejection by 12months post-transplant among the unrelated compared to the related group in IgA (10.1% vs. 6.5%, p<0.001), FSGS (12.1% vs. 10%, p-0.016), and lupus nephritis (11.8% vs. 9.2%; p-0.049). The biological donor-recipient relationship was not associated with a worse recipient or graft survival or death with functioning graft in the multivariable models. These findings are consistent with the known benefits of living-related-donor kidney transplants and counter the reports of the potential adverse impact of the donor-recipient biologic relationship on allograft outcomes.

Inhibition of DAI refrains dendritic cells from maturation and prolongs murine islet and skin allograft survival.

Central to allograft rejection is the T cell-mediated adaptive immune response initiated by activated dendritic cells (DCs). Previous studies have shown that the DNA-dependent activator of IFN regulatory factors (DAI) is involved in the maturation and activation of DCs. Therefore, we hypothesized that inhibition of DAI could prevent DCs from maturation and prolong murine allograft survival. Donor mouse bone marrow-derived dendritic cells (BMDCs) were transduced with the recombinant adenovirus vector (AdV-DAI-RNAi-GFP) to inhibit DAI expression (DC-DAI-RNAi), and the immune cell phenotype and function of DC-DAI-RNAi upon lipopolysaccharide (LPS) stimulation were evaluated. Then DC-DAI-RNAi was injected into recipient mice before islet transplantation and skin transplantation. The survival times of islet and skin allograft were recorded and the proportions of T cell subsets in spleen and secretion levels of cytokines in serum were measured. We identified that DC-DAI-RNAi inhibited the expression of main co-stimulatory molecules and MHC-II, exhibited strong phagocytic ability, and secreted high levels of immunosuppressive cytokines and low levels of immunostimulating cytokines. Recipient mice treated with DC-DAI-RNAi had longer islet and skin allograft survival times. In the murine islet transplantation model, we observed an increase in Treg cells proportion, a reduction in Th1 and Th17 cells proportions in spleen, and similar trends in their secreted cytokines in serum in the DC-DAI-RNAi group. Inhibition of DAI by adenovirus transduction inhibits the maturation and activation of DCs, affects the differentiation of T cell subsets as well as their secreted cytokines, and prolongs allograft survival.

Multidrug-resistant Klebsiella Pneumoniae Infection Led to Resection of the Graft in a Small Bowel Transplant Recipient: A Case Report and Review of the Literature

Infection due to multidrug-resistant Klebsiella pneumoniae is a common cause of graft resection after small bowel transplantation. We report a failed case in which the intestinal graft was resected 18 days after the operation due to postoperative infection with multidrug-resistant K pneumoniae and a literature review of other common causes of small bowel transplantation failure have been reported. A female, 29 years of age, underwent partial living small bowel transplantation for short bowel syndrome. After the operation, the patient was infected with multidrug-resistant K pneumoniae, even though various anti-infective regimens were employed. It further developed into sepsis and disseminated into intravascular coagulation, leading to exfoliation and necrosis of the intestinal mucosa. Finally, the intestinal graft had to be resected to save the patient's life. Multidrug-resistant K pneumoniae infection often affects the biological function of intestinal grafts and can even lead to necrosis. Other common causes of failure, including postoperative infection, rejection, post-transplantation lymphoproliferative disorder, graft-vs-host disease, surgical complications, and other related diseases, were also discussed throughout the literature review. Pathogenesis due to diverse and interrelated factors makes the survival of intestinal allografts a great challenge. Therefore, only by fully understanding and mastering the common causes of surgical failure can the success rate of small bowel transplantation be effectively improved.

Assessment of donor compatibility in human solid organ transplantation and evaluation of allogeneic responses using a novel humanized mouse model.

Abstract The end result of solid organ transplantation is dictated by selection of a well-matched donor, leading to allograft survival. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching results in poor graft acceptance, inflammation and rejection. The current evaluations for donor-recipient HLA incompatibility does not provide adequate information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a novel method for analysis of alloimmune responsiveness between donor and recipient in vivoby introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient’s personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing and mixed lymphocyte reaction (MLR) for assessment of allogeneic response was indistinguishable between 2 related donors of the recipient. Contrastingly in recipient’s humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with increased infiltration of cytotoxic GzmB +CD8 +T cells. Moreover, the same donor induced upregulation of genes involved in the allograft rejection identified by transcriptomic analysis of graft infiltrating CD45 +cells. Humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in transplantation. This approach can be used to evaluate alloresponses in cell based therapies as well. This study was supported by research funding from the Carlos and Marguerite Mason Trust, and by U.S. National Institutes of Health, National Cancer Institute Grant CA 172230

Oral administration of the commensal Alistipes onderdonkiiprolongs allograft survival

Abstract Intestinal commensals can exert immunomodulatory effects on the host, with beneficial or detrimental consequences depending on underlying diseases. We have previously identified a specific commensal, Alistipes onderdonkii, as mediator of prolonged allograft survival and reduced alloimmunity. Here, we investigated its sufficiency and mechanism of action and found that oral administration of a beneficial A. onderdonkii strain DSM19147 but not a neutral strain, DSM108265, was sufficient to delay minor mismatched skin graft rejection in a TNF-dependent manner. Specifically, DSM19147 decreased TNF production in T cells and antigen-presenting cells, and TNF neutralization prolonged graft survival. Metagenomics and metabolomics analyses between DSM19147 versus strains that did not prolong graft survival identified unique genes and metabolites correlated with the anti-inflammatory effect of DSM19147. Candidate metabolic pathways unique to DSM19147 pointed to sialic acid and KDO2-lipid A modifications. Our findings identify A. onderdonkii DSM19147 as an anti-inflammatory probiotic that improves transplant survival. Supported by NIAID grant 2R01AI115716 to MLA, NIAID grant 1U01AI132898 to MLD and DP, NIDDK grant TL1DK132769 to MR, NIAID grant 5T32AI007090 to MS and MK, and by the Growth, Development, and Disabilities Training Program grant (T32 HD007009) to CM.

Sel1-like proteins and peptides are the major Oxalobacter formigenes-derived factors stimulating oxalate transport by human intestinal epithelial cells.

Kidney stones (KSs) are very common, excruciating, and associated with tremendous healthcare cost, chronic kidney disease (CKD), and kidney failure (KF). Most KSs are composed of calcium oxalate and small increases in urinary oxalate concentration significantly enhance the stone risk. Oxalate also potentially contributes to CKD progression, kidney disease-associated cardiovascular diseases, and poor renal allograft survival. This emphasizes the urgent need for plasma and urinary oxalate lowering therapies, which can be achieved by enhancing enteric oxalate secretion. We previously identified Oxalobacter formigenes (O. formigenes)-derived factors secreted in its culture-conditioned medium (CM), which stimulate oxalate transport by human intestinal Caco2-BBE (C2) cells and reduce urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. Given their remarkable therapeutic potential, we now identified Sel1-like proteins as the major O. formigenes-derived secreted factors using mass spectrometry and functional assays. Crystal structures for six proteins were determined to confirm structures and better understand functions. OxBSel1-14-derived small peptides P8 and P9 were identified as the major factors, with P8 + 9 closely recapitulating the CM's effects, acting through the oxalate transporters SLC26A2 and SLC26A6 and PKA activation. Besides C2 cells, P8 + 9 also stimulate oxalate transport by human ileal and colonic organoids, confirming that they work in human tissues. In conclusion, P8 and P9 peptides are identified as the major O. formigenes-derived secreted factors and they have significant therapeutic potential for hyperoxalemia, hyperoxaluria, and related disorders, impacting the outcomes of patients suffering from KSs, enteric hyperoxaluria, primary hyperoxaluria, CKD, KF, and renal transplant recipients.NEW & NOTEWORTHY We previously identified Oxalobacter formigenes-derived secreted factors stimulating oxalate transport by human intestinal epithelial cells in vitro and reducing urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. We now identified Sel1-like proteins and small peptides as the major secreted factors and they have significant therapeutic potential for hyperoxalemia and hyperoxaluria, impacting the outcomes of patients suffering from kidney stones, primary and secondary hyperoxaluria, chronic kidney disease, kidney failure, and renal transplant recipients.

Monomethyl fumarate prevents alloimmune rejection in mouse heart transplantation by inducing tolerogenic dendritic cells.

Dendritic cells (DCs) are important targets for eliciting allograft rejection after transplantation. Previous studies have demonstrated that metabolic reprogramming of DCs can transform their immune functions and induce their differentiation into tolerogenic DCs. In this study, we aim to investigate the protective effects and mechanisms of monomethyl fumarate (MMF), a bioactive metabolite of fumaric acid esters, in a mouse model of allogeneic heart transplantation. Bone marrow-derived DCs are harvested and treated with MMF to determine the impact of MMF on the phenotype and immunosuppressive function of DCs by flow cytometry and T-cell proliferation assays. RNA sequencing and Seahorse analyses are performed for mature DCs and MMF-treated DCs (MMF-DCs) to investigate the underlying mechanism. Our results show that MMF prolongs the survival time of heart grafts and inhibits the activation of DCs in vivo. MMF-DCs exhibit a tolerogenic phenotype and function in vitro. RNA sequencing and Seahorse analyses reveal that MMF activates the Nrf2 pathway and mediates metabolic reprogramming. Additionally, MMF-DC infusion prolongs cardiac allograft survival, induces regulatory T cells, and inhibits T-cell activation. MMF prevents allograft rejection in mouse heart transplantation by inducing tolerogenic DCs.

A new slow-releasing formulation of butyrate prolongs allograft survival

Abstract The microbiota consists of diverse microbes producing metabolites that can influence the immune system locally as well as systemically. These bioactive metabolites (postbiotics) have therapeutic potential and may prove useful to facilitate graft acceptance. Short-chain fatty acids (SCFA) promote intestinal homeostasis and have been linked to health and disease. The Hubbell-Nagler laboratories at the University of Chicago have developed a micelle-based platform that can deliver the SCFA butyrate systemically, with long-term retention and induction of tolerogenic responses. We hypothesized that the administration of this butyrate formulation will improve graft survival by suppressing the alloimmune response. Our preliminary data showed that only oral delivery of the butyrate formulation prolonged survival of a C57Bl/6 male to female minor-mismatched skin graft significantly, whereas sub-cutaneous and intra-peritoneal administration were ineffective. Improved graft survival was associated with diminished production of TNFα by splenic and skin-draining lymph node myeloid cells upon LPS stimulation, suggesting that butyrate modulates the myeloid compartment to reduce levels of pro-inflammatory cytokines. The postbiotic also enhanced survival of a BALB/c to C57Bl/6 major-mismatched skin graft, without the use of immunosuppressive drugs, and resulted in lower levels of donor-specific alloantibodies. Prolonging the administration of butyrate post-transplantation ameliorated graft survival even further, confirming the micelle-based platform has therapeutic potential. Current efforts focus on determining if the butyrate formulation drives myeloid cell polarization toward an anti-inflammatory phenotype. This project was supported by grant NIH/NIAID 2R01AI115716

Toward transplantation tolerance with adipose tissue-derived therapeutics.

Solid organ and composite tissue allotransplanation have been widely applied to treat end-stage organ failure and massive tissue defects, respectively. Currently there are a lot of research endeavors focusing on induction of transplantation tolerance, to relieve the burden derived from long-term immunosuppressant uptake. The mesenchymal stromal cells (MSCs) have been demonstrated with potent immunomodulatory capacities and applied as promising cellular therapeutics to promote allograft survival and induce tolerance. As a rich source of adult MSCs, adipose tissue provides additional advantages of easy accessibility and good safety profile. In recent years, the stromal vascular fraction (SVF) isolated from adipose tissues following enzymatic or mechanical processing without in vitro culture and expansion has demonstrated immunomodulatory and proangiogenic properties. Furthermore, the secretome of AD-MSCs has been utilized in transplantation field as a potential "cell-free" therapeutics. This article reviews recent studies that employ these adipose-derived therapeutics, including AD-MSCs, SVF, and secretome, in various aspects of organ and tissue allotransplantation. Most reports validate their efficacies in prolonging allograft survival. Specifically, the SVF and secretome have performed well for graft preservation and pretreatment, potentially through their proangiogenic and antioxidative capacities. In contrast, AD-MSCs were suitable for peri-transplantation immunosuppression. The proper combination of AD-MSCs, lymphodepletion and conventional immunosuppressants could consistently induce donor-specific tolerance to vascularized composite allotransplants (VCA). For each type of transplantation, optimizing the choice of therapeutics, timing, dose, and frequency of administration may be required. Future progress in the application of adipose-derived therapeutics to induce transplantation tolerance will be further benefited by continued research into their mechanisms of action and the development of standardized protocols for isolation methodologies, cell culture, and efficacy evaluation.

Safety, efficacy, and timing of transplantation(s) in propionic and methylmalonic aciduria.

Propionic (PA) and methylmalonic aciduria (MMA) share many clinical similarities, which include the risk of acute metabolic encephalopathies, and some long-term complications, such as optic neuropathy, pancreatic involvement, developmental disability, and similar management approaches, but they also represent distinct clinical and biochemical entities. In the severe forms of PA and MMA, most long-term complications cannot be prevented with conventional clinical management. Organ transplantation represents a form of partial enzyme replacement to improve the long-term outlook for these disorders. There is evidence that early liver transplant in both disorders greatly improves metabolic stability and reduces the risk of long-term complications. For MMA, early liver transplant reduces methylmalonic acid levels which in turns reduces its effects on kidneys, and therefore slows progression of chronic kidney disease. However, established organ damage cannot be reversed. For patients with MMA who present with chronic kidney disease, consideration should be given for combined liver and kidney transplants. Transplantation in PA and MMA carries a high risk of complications and requires highly specialised pre-operative and peri-operative management. Involvement of a multidisciplinary team is essential and should include metabolic team, nephrologist, hepatologist, hepatobiliary and renal transplant surgeons, anaesthesiologists, cardiologists, intensive care team, dieticians and specialist nurses. These patients require life-long multidisciplinary follow-up. There is increasing evidence in the literature on excellent short to medium-term patient and allograft survival following transplantation when patients are managed by a multidisciplinary team in a specialist centre. Improved early diagnosis and reductions in transplant-related mortality and morbidity have allowed early transplantation to be used electively to further improve the outcome.