Donor antigen-specific regulatory T cell administration to recipients of live donor kidneys: A ONE Study consortium pilot trial.

Regulatory T cells (Tregs) can inhibit cellular immunity in diverse experimental models and have entered early phase clinical trials in autoimmunity and transplantation to assess safety and efficacy. As part of the ONE Study consortium, we conducted a phase I-II clinical trial in which purified donor antigen reactive (dar)-Tregs (CD4CD25CD127) were administered to 3 patients, 7 to 11 days after live donor renal transplant. Recipients received a modified immunosuppression regimen, without induction therapy, consisting of maintenance tacrolimus, mycophenolate mofetil, and steroids.

Suppression of allograft rejection by regulatory B cells induced via TLR signaling.

B lymphocytes have long been recognized for their critical contributions to adaptive immunity, providing defense against pathogens through cognate antigen presentation to T cells and Ab production. More recently appreciated is that B cells are also integral in securing self-tolerance; this has led to interest in their therapeutic application to downregulate unwanted immune responses, such as transplant rejection. In this study, we found that PMA- and ionomycin-activated mouse B cells acquire regulatory properties following stimulation through TLR4/TLR9 receptors (Bregs-TLR).

Transplantation in the Age of Precision Medicine: The Emerging Field of Treg Therapy.

Solid organ transplantation has experienced incredible success over the past half century in rescuing patients with end-stage organ failure and bestowing them with a high quality of life. This success in large part is the result of advances in immunosuppression, however, these regimens come with significant costs including opportunistic infections, and in some cases, direct toxicity to the newly transplanted organs. Further advances are needed.

Intrapleural transplantation of allogeneic pancreatic islets achieves glycemic control in a diabetic non-human primate.

Clinical islet transplantation has relied almost exclusively on intraportal administration of pancreatic islets, as it has been the only consistent approach to achieve robust graft function in human recipients. However, this approach suffers from significant loss of islet mass from a potent immediate blood-mediated inflammatory response (IBMIR) and a hypoxic environment. To avoid these negative aspects of the portal site, we explored an alternative approach in which allogeneic islets were transplanted into the intrapleural space of a non-human primate (NHP), treated with an immunosuppression regimen previously reported to secure routine survival and tolerance to allogeneic islets in NHP.

Kidney transplantation from triple-knockout pigs expressing multiple human proteins in cynomolgus macaques.

Porcine cells devoid of three major carbohydrate xenoantigens, αGal, Neu5GC, and SDa (TKO) exhibit markedly reduced binding of human natural antibodies. Therefore, it is anticipated that TKO pigs will be better donors for human xenotransplantation. However, previous studies on TKO pigs using old world monkeys (OWMs) have been disappointing because of higher anti-TKO pig antibodies in OWMs than humans.

Properties of regulatory B cells regulating B cell targets.

Regulatory B cells (Bregs) have shown promise as anti-rejection therapy applied to organ transplantation. However, less is known about their effect on other B cell populations that are involved in chronic graft rejection. We recently uncovered that naïve B cells, stimulated by TLR ligand agonists, converted into B cells with regulatory properties (Bregs-TLR) that prevented allograft rejection.

Machine Perfusion of the Liver: A Review of Clinical Trials.

Although efforts have been made by transplant centers to increase the pool of available livers by extending the criteria of liver acceptance, this practice creates risks for recipients that include primary non-function of the graft, early allograft dysfunction and post-operative complications. Donor liver machine perfusion (MP) is a promising novel strategy that not only decreases cold ischemia time, but also serves as a method of assessing the viability of the graft. In this review, we summarize the data from liver machine perfusion clinical trials and discuss the various techniques available to date as well as future applications of machine perfusion.

TGF-β-secreting regulatory B cells: unsung players in immune regulation.

Regulatory B cells contribute to the regulation of immune responses in cancer, autoimmune disorders, allergic conditions and inflammatory diseases. Although most studies focus on regulatory B lymphocytes expressing interleukin-10, there is growing evidence that B cells producing transforming growth factor β (TGF-β) can also regulate T-cell immunity in inflammatory diseases and promote the emergence of regulatory T cells that contribute to the induction and maintenance of natural and induced immune tolerance. Most research on TGF-β regulatory B cells has been conducted in models of allergy, cancer and autoimmune diseases, but there has, as yet, been limited scrutiny of their role in the transplant setting.

Practitioner availability rather than surgical quality impacts the utilization of liver transplantation for hepatocellular carcinoma.

Background: Liver transplantation (LT) provides better outcome than surgical resection (SR) although both are acceptable surgical options for hepatocellular carcinoma (HCC). It is unclear whether non-clinical factors drive treatment decisions. Our goal is to identify factors that may affect treatment decisions.

Detection of alloreactive T cells from cryopreserved human peripheral blood mononuclear cells.

Precise analyses of alloreactive T cell phenotype and function can inform both the nature and intensity of adaptive responses to transplant antigens. However, alloreactive T cells are sparse and difficult to detect, particularly in cryopreserved peripheral blood mononuclear cells (PBMCs) and from hypo-responsive individuals. An assay to identify and phenotype alloreactive cells would be particularly valuable, especially for multi-center clinical trials that often store frozen samples for batch analysis.

Multi-Center Analysis of Liver Transplantation for Combined Hepatocellular Carcinoma-Cholangiocarcinoma Liver Tumors.

Background: Combined hepatocellular-cholangiocarcinoma liver tumors (cHCC-CCA) with pathologic differentiation of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma within the same tumor are not traditionally considered for liver transplantation due to perceived poor outcomes. Published results are from small cohorts and single centers. Through a multicenter collaboration, we performed the largest analysis to date of the utility of liver transplantation for cHCC-CCA.

Current status of porcine islet xenotransplantation.

Purpose Of Review: Human islet transplantation has proven to be a highly effective treatment for patients with labile type 1 diabetes mellitus, which can free patients from daily glucose monitoring and insulin injections. However, the shortage of islet donors limits its' broad application. Porcine islet xenotransplantation presents a solution to the donor shortage and recent advances in genetic modification and immunosuppressive regimens provide renewed enthusiasm for the potential of this treatment.

Regulatory B cells require antigen recognition for effective allograft tolerance induction.

Through multiple mechanisms, regulatory B cells (Breg) have been shown to play an important role in the development of allograft tolerance. However, a careful understanding of the role of antigen-specificity in Breg-mediated allograft tolerance has remained elusive. In experimental models of islet and cardiac transplantation, it has been established that Bregs can be induced in vivo by anti-CD45RB ± anti-TIM1antibody treatment, resulting in prolonged, Breg-dependent allograft tolerance.

Do Social Determinants Define "Too Sick" to Transplant in Patients With End-stage Liver Disease?

Background: Delisting for being "too sick" to be transplanted is subjective. Previous work has demonstrated that the mortality of patients delisted for "too sick" is unexpectedly low. Transplant centers use their best clinical judgment for determining "too sick," but it is unclear how social determinants influence decisions to delist for "too sick.

Current state of organ transplant tolerance.

Purpose Of Review: Immunological tolerance has long been considered the 'holy grail' of organ transplantation. Although tolerance has been an active area of research for 70 years, its clinical application has only been possible in the last two decades and widespread use remains an, as yet, unattained goal. Recent advances in the understanding of immune regulation have identified many new approaches to tolerance induction and several clinical trials are currently aimed at bringing this treatment to more patients.

Health Literacy Burden Is Associated With Access to Liver Transplantation.

Background: Getting listed for liver transplantation is a complex process. Institutional health literacy may influence the ability of patients with limited educational attainment (EA) to list. As an easily accessible indicator of institutional health literacy, we measured the understandability of liver transplant center education websites and assessed whether there was any association with the percentage of low EA patients on their waitlists.

A surprising cross-species conservation in the genomic landscape of mouse and human oral cancer identifies a transcriptional signature predicting metastatic disease.

Purpose: Improved understanding of the molecular basis underlying oral squamous cell carcinoma (OSCC) aggressive growth has significant clinical implications. Herein, cross-species genomic comparison of carcinogen-induced murine and human OSCCs with indolent or metastatic growth yielded results with surprising translational relevance.

Experimental Design: Murine OSCC cell lines were subjected to next-generation sequencing (NGS) to define their mutational landscape, to define novel candidate cancer genes, and to assess for parallels with known drivers in human OSCC.

Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting.

Cancer immunoediting, the process by which the immune system controls tumour outgrowth and shapes tumour immunogenicity, is comprised of three phases: elimination, equilibrium and escape. Although many immune components that participate in this process are known, its underlying mechanisms remain poorly defined. A central tenet of cancer immunoediting is that T-cell recognition of tumour antigens drives the immunological destruction or sculpting of a developing cancer.