Assessing the potential of angiotensin II type 1 receptor and donor specific anti-endothelial cell antibodies to predict long-term kidney graft outcome.

Endothelial cell antigens have been reported as potential targets for antibodies in the context of organ transplantation, leading to increased risk for graft failure. Serum samples from 142 consecutive living donor kidney recipients were tested for the presence of antibodies to angiotensin II - type 1 receptor (AT1R), donor endothelial cells, and donor HLA. Graft survival was monitored for five years post-transplant, and secondary outcomes, including biopsy-proven rejection, proteinuria, biopsy-proven vasculopathy, and renal function based on serum creatinine were also assessed for the first two to three years. AT1R antibody levels were positive (>17U/mL) in 11.3%, 18.8% and 8.1% of patients pre-transplant, post-transplant and at time of indication biopsy, respectively. XM-ONE assay was positive in 17.6% of patients pre-transplant (7 IgG+; 15 IgM+; 3 IgG+/IgM+). Overall, 4 patients experienced antibody-mediated rejection (AMR), 31 borderline cellular rejection (BCR), 19 cellular rejection (CR) and 3 mixed AMR and CR within the first 24months. While pre-existing and de novo donor-specific HLA antibodies were associated with graft failure and many secondary outcomes, no statistical association was found for either anti-endothelial or anti-AT1R antibodies, indicating that these tests may not be the best predictors of graft outcome in living donor renal transplantation.

Metabolic reprogramming of alloantigen-activated T cells after hematopoietic cell transplantation.

Alloreactive donor T cells are the driving force in the induction of graft-versus-host disease (GVHD), yet little is known about T cell metabolism in response to alloantigens after hematopoietic cell transplantation (HCT). Here, we have demonstrated that donor T cells undergo metabolic reprograming after allogeneic HCT. Specifically, we employed a murine allogeneic BM transplant model and determined that T cells switch from fatty acid ß-oxidation (FAO) and pyruvate oxidation via the tricarboxylic (TCA) cycle to aerobic glycolysis, thereby increasing dependence upon glutaminolysis and the pentose phosphate pathway. Glycolysis was required for optimal function of alloantigen-activated T cells and induction of GVHD, as inhibition of glycolysis by targeting mTORC1 or 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) ameliorated GVHD mortality and morbidity. Together, our results indicate that donor T cells use glycolysis as the predominant metabolic process after allogeneic HCT and suggest that glycolysis has potential as a therapeutic target for the control of GVHD.

Detection of donor-specific antibodies in kidney transplantation.

INTRODUCTION: Precise and timely detection of human leukocyte antigen (HLA) donor-specific antibodies (DSAs) is vital for evaluating humoral immune status of patients pre- and post-transplantation. SOURCE OF DATA: Clinically relevant articles on theory, development, methodology and application of HLA-DSA testing in kidney transplantation. AREAS OF AGREEMENT AND CONTROVERSY: The availability of solid phase HLA-antibody testing revolutionized our ability to detect HLA-DSA and to appreciate their significance in kidney transplant outcome. The best approach to determine the strength, immunogenicity and pathogenicity of HLA antibodies still remains controversial. GROWING POINTS: Assays to identify complement-binding antibodies were developed. Their clinical utilization, pre- and post-transplantation, is currently under investigation. Appreciation of the complexity of HLA-DQ antibodies should lead to better assignment of unacceptable antibodies and cPRA calculation. AREAS TIMELY FOR DEVELOPING RESEARCH: Characterization of HLA-antibody epitopes, and utilization of epitope matching to better define compatible donors could contribute to better transplant outcomes.

Pharmacologic inhibition of PKCα and PKCθ prevents GVHD while preserving GVL activity in mice.

Allogeneic hematopoietic cell transplantation (HCT) is the most effective therapy for hematopoietic malignancies through T-cell-mediated graft-vs-leukemia (GVL) effects but often leads to severe graft-vs-host disease (GVHD). Given that protein kinase Cθ (PKCθ), in cooperation with PKCα, is essential for T-cell signaling and function, we have evaluated PKCθ and PKCα as potential therapeutic targets in allogeneic HCT using genetic and pharmacologic approaches. We found that the ability of PKCα(-/-)/θ(-/-) donor T cells to induce GVHD was further reduced compared with PKCθ(-/-) T cells in relation with the relevance of both isoforms to allogeneic donor T-cell proliferation, cytokine production, and migration to GVHD target organs. Treatment with a specific inhibitor for both PKCθ and PKCα impaired donor T-cell proliferation, migration, and chemokine/cytokine production and significantly decreased GVHD in myeloablative preclinical murine models of allogeneic HCT. Moreover, pharmacologic inhibition of PKCθ and PKCα spared T-cell cytotoxic function and GVL effects. Our findings indicate that PKCα and θ contribute to T-cell activation with overlapping functions essential for GVHD induction while less critical to the GVL effect. Thus, targeting PKCα and PKCθ signaling with pharmacologic inhibitors presents a therapeutic option for GVHD prevention while largely preserving the GVL activity in patients receiving HCT.