Eliminating financial disincentives to living kidney donation - a call to action.

The incidence of end stage renal disease (ESRD) in the United States (US) is increasing each year. The lone curative treatment for ESRD remains kidney transplantation. Despite the demonstrated medical and economic benefits, living donor kidney transplantation (LDKT) only accounts for a small number of kidney transplantations each year.

Large Animal Models of Vascularized Composite Allotransplantation: A Review of Immune Strategies to Improve Allograft Outcomes.

Over the past twenty years, significant technical strides have been made in the area of vascularized composite tissue allotransplantation (VCA). As in solid organ transplantation, the allogeneic immune response remains a significant barrier to long-term VCA survival and function. Strategies to overcome acute and chronic rejection, minimize immunosuppression and prolong VCA survival have important clinical implications.

Non-invasive imaging for the diagnosis of acute rejection in transplantation: The next frontier.

Acute rejection is a leading cause of organ transplant failure and the most common indication for re-transplantation. Clinically, suspicion of acute rejection is often dependent upon serum laboratory values which may only manifest after organ injury. The gold standard for diagnosis requires an invasive biopsy which can carry serious clinical risks including bleeding and graft loss as well as the possibility of sampling error.

Cellular Immunotherapies in Preclinical Large Animal Models of Transplantation.

Hematopoietic stem cell (HSC) transplantation and solid organ transplantation remain the only curative options for many hematologic malignancies and end-stage organ diseases. Unfortunately, the sequelae of long-term immunosuppression, as well as acute and chronic rejection, carry significant morbidities, including infection, malignancy, and graft loss. Numerous murine models have demonstrated the efficacy of adjunctive cellular therapies using HSCs, regulatory T cells, mesenchymal stem cells, and regulatory dendritic cells in modulating the alloimmune response in favor of graft tolerance; however, translation of such murine approaches to other preclinical models and in the clinic has yielded mixed results.

Programmed T cell differentiation: Implications for transplantation.

While T cells play a critical role in protective immunity against infection, they are also responsible for graft rejection in the setting of transplantation. T cell differentiation is regulated by both intrinsic transcriptional pathways as well as extrinsic factors such as antigen encounter and the cytokine milieu. Herein, we review recent discoveries in the transcriptional regulation of T cell differentiation and their impact on the field of transplantation.

Impact of selective CD28 blockade on virus-specific immunity to a murine Epstein-Barr virus homolog.

CTLA-4Ig (belatacept) blocks the CD80/CD86 ligands for both CD28 and CTLA-4; thus, in addition to the intended effect of blocking CD28-mediated costimulation, belatacept also has the unintended effect of blocking CTLA-4-mediated coinhibition. Recently, anti-CD28 domain antibodies (dAb) that selectively target CD28 while leaving CTLA-4 intact were shown to more effectively inhibit alloimmune responses and prolong graft survival. However, the impact of selective CD28 blockade on protective immunity has not been extensively investigated.

Sepsis erodes CD8 memory T cell-protective immunity against an EBV homolog in a 2B4-dependent manner.

Epstein-Barr virus (EBV) reactivation commonly occurs following sepsis, but the mechanisms underlying this are unknown. We utilized a murine EBV homolog (gHV) and the cecal ligation and puncture model of polymicrobial sepsis to study the impact of sepsis on gHV reactivation and CD8 T cell immune surveillance following a septic insult. We observed a significant increase in the frequency of gHV-infected germinal center B cells on day 7 following sepsis.

Challenges and opportunities in targeting the CD28/CTLA-4 pathway in transplantation and autoimmunity.

T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. Areas covered: This review discusses past, current and future biological therapies that have been utilized to block the CD28/CTLA-4 cosignaling pathway in the settings of autoimmunity and transplantation, as well the challenges facing successful implementation of these therapies.

Donor Lymphocyte Infusion-Mediated Graft-versus-Host Responses in a Preclinical Swine Model of Haploidentical Hematopoietic Cell Transplantation.

We previously described successful hematopoietic stem cell engraftment across MHC barriers in miniature swine without graft-versus-host disease (GVHD) using novel reduced-intensity conditioning regimens consisting of partial transient recipient T cell-depletion, thymic or low-dose total body irradiation, and a short course of cyclosporine A. Here we report that stable chimeric animals generated with these protocols are strongly resistant to donor leukocyte infusion (DLI)-mediated GVH effects. Of 33 total DLIs in tolerant chimeras at clinical doses, 21 failed to induce conversion to full donor hematopoietic chimerism or cause GVHD.

MicroRNA miR-155 Is Necessary for Efficient Gammaherpesvirus Reactivation from Latency, but Not for Establishment of Latency.

Unlabelled: MicroRNA-155 (miR-155) has been shown to play significant roles in the immune response, including in the formation of germinal centers (GC) and the development and maturation of T follicular helper (Tfh) cells. There is in vitro evidence to support a critical role for cellular miR-155 and viral miR-155 homologs in the establishment of gammaherpesvirus latency in B cells. We sought to determine the contribution of miR-155 to the establishment and maintenance of latency in vivo using murine gammaherpesvirus (MHV-68) infection.

CD4 and CD8 T cells directly recognize murine gammaherpesvirus 68-immortalized cells and prevent tumor outgrowth.

There has been extensive research regarding T cell recognition of Epstein-Barr virus-transformed cells; however, less is known regarding the recognition of B cells immortalized by gamma-2 herpesviruses. Here we show that B cells immortalized by murine gammaherpesvirus 68 (MHV-68, γHV-68) can be controlled by either CD4 or CD8 T cells in vivo. We present evidence for the direct recognition of infected B cells by CD4 and CD8 T cells.

Effects of mobilization regimens in donors on outcomes of hematopoietic cell transplantation in miniature Swine.

Toxicities and complications associated with hematopoietic cell transplantation currently limit this potentially curative therapy for malignant and nonmalignant blood disorders. Miniature swine provide a clinically relevant model for studies to improve posttransplantation outcomes. Miniature swine recipients of high-dose haploidentical hepatopoietic cell transplantation after reduced-intensity conditioning consisting of low-dose (100 cGy) total-body irradiation, partial T-cell depletion by using a CD3 immunotoxin, and a 45-d course of cyclosporine A typically successfully engraft without graft-versus-host disease.

Expression and purification of non-N-glycosylated porcine interleukin 3 in yeast Pichia pastoris.

Yeast Pichia pastoris has been widely utilized to express heterologous recombinant proteins. P. pastoris expressed recombinant porcine interleukin 3 (IL3) has been used for porcine stem cell mobilization in allo-hematopoietic cell transplantation models and pig-to-primate xeno-hematopoietic cell transplantation models in our lab for many years.