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.

Selective CD28 blockade impacts T cell differentiation during homeostatic reconstitution following lymphodepletion.

Introduction: Costimulation blockade targeting the CD28 pathway provides improved long-term renal allograft survival compared to calcineurin inhibitors but may be limited as CTLA-4-Ig (abatacept, belatacept) blocks both CD28 costimulation and CTLA-4 coinhibition. Directly targeting CD28 while leaving CTLA-4 intact may provide a mechanistic advantage. Fc-silent non-crosslinking CD28 antagonizing domain antibodies (dAb) are currently in clinical trials for renal transplantation.

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.

Edema and tetraparesis in a miniature pig after allogeneic hematopoietic cell transplantation.

A 3-mo-old, 12-kg, intact, miniature pig presented with severe neurologic signs on day 8 after hematopoietic cell transplantation. This pig had received an immunosuppressive regimen before transplantation that included an antiCD3 immunotoxin for T-cell depletion, 100 cGy of total-body irradiation, and cyclosporine for 45 d. The pig began exhibiting erythematous lesions on posttransplantation day 7.

Lack of antidonor alloantibody does not indicate lack of immune sensitization: studies of graft loss in a haploidentical hematopoietic cell transplantation swine model.

Loss of chimerism is an undesirable outcome of allogeneic hematopoietic cell transplantation (HCT) after reduced-intensity conditioning. Understanding the nature of cellular and humoral immune responses to HCT after graft loss could lead to improved retransplantation strategies. We investigated the immunologic responses after graft loss in miniature swine recipients of haploidentical HCT that received reduced-intensity conditioning.

Effect of pre-existing anti-diphtheria toxin antibodies on T cell depletion levels following diphtheria toxin-based recombinant anti-monkey CD3 immunotoxin treatment.

Diphtheria toxin (DT)-based anti-CD3 immunotoxins have clinical relevance in numerous applications including autoimmune disease therapies and organ transplantation tolerance protocols. Pre-existing anti-DT antibodies acquired either by vaccination against diphtheria toxin or infections with C. diphtheriae may interfere or inhibit the function of these anti-CD3 immunotoxins.

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.

Development of a diphtheria toxin based antiporcine CD3 recombinant immunotoxin.

Anti-CD3 immunotoxins, which induce profound but transient T-cell depletion in vivo by inhibiting eukaryotic protein synthesis in CD3+ cells, are effective reagents in large animal models of transplantation tolerance and autoimmune disease therapy. A diphtheria toxin based antiporcine CD3 recombinant immunotoxin was constructed by fusing the truncated diphtheria toxin DT390 with two identical tandem single chain variable fragments (scFv) derived from the antiporcine CD3 monoclonal antibody 898H2-6-15. The recombinant immunotoxin was expressed in a diphtheria-toxin resistant yeast Pichia pastoris strain under the control of the alcohol oxidase promoter.