The Thomas E. Starzl Transplantation Institute is a leader in cutting-edge research.
Our basic scientists, clinical researchers, and clinicians dedicate countless hours to making research discoveries that will positively impact the world’s transplant community.
Featured Publications
Interleukin-21 promotes Type-1 activation and cytotoxicity of CD56dimCD16bright natural killer cells during kidney allograft antibody–mediated rejection showing a new link between adaptive and innate humoral allo-immunity
Abstract: View Article – The role of Natural killer (NK) cells during kidney allograft antibody–mediated rejection (ABMR) is increasingly recognized, but an in-depth characterization of mechanisms that contribute to such immune response is still under investigation. Here, we characterized phenotypic, functional, and transcriptomic profiles of peripheral blood circulating and allograft infiltrating CD56dimCD16bright NK cells during anti-HLA donor-specific antibody (DSA)+ ABMR. Cross-sectional analyses performed in 71 kidney transplant recipients identified a unique phenotypic circulating CD56dimCD16bright NK cell cluster expanded in DSA+ ABMR. This cluster co-expressed high levels of the interleukin-21 Receptor (IL-21R); Type-1 transcription factors T-bet and EOMES, CD160 and natural killer group 2D cytotoxic and activating co-stimulatory receptors. CD160+ IL-21R+ NK cells correlated with elevated plasma IL-21, Ki-67+ ICOS+ (CD278) IL-21-producing circulating T follicular helper cells, enhanced Type-1 pro-inflammatory cytokines, NK cell cytotoxicity, worse microvascular inflammation and graft loss. Single-cell transcriptomic analysis of circulating NK cells delineated an expanded cluster in DSA+ ABMR characterized by elevated pro-inflammatory/cytotoxic pathways, IL-21/STAT3 signaling, and leukocyte trans-endothelial migration pathways. Infiltration of CD160+ IL-21R+ NK cells with similar transcriptomic profile was detected in DSA+ ABMR allograft biopsies, potentially contributing to allograft injury. Thus, the IL-21/IL-21R axis, linking adaptive and innate humoral allo-immunity, or NK
Translational B cell Cytokines Risk Stratify Early Borderline Rejection After Renal Transplantation
Abstract: View Article – Borderline rejection (BL) in renal transplantation is associated with decreased allograft survival, yet many patients with BL maintain stable graft function. Identifying patients with early BL at-risk for
Multiple infusions of ex vivo-expanded regulatory T cells promote CD163+ myeloid cells and kidney allograft survival in non-lymphodepleted non-human primates
Author: Kazuki Sasaki, Masahiko Kubo, Yu-chao Wang, Lien Lu, Veronica Vujevich, Michelle Wood-Trageser, Kayla Golnoski, Andrew Lesniak, Vikraman Gunabushanam, Armando Ganoza, Martin Wijkstrom, Abhinav Humar, Anthony Demetris, Angus Thomson, Mohamed Ezzelarab
Abstract: View Article – Clinical verification of adoptively transferred regulatory T cell (Treg) efficacy in transplantation remains challenging. Here, we examined the influence of autologous ex vivo-expanded polyclonal Tregs on kidney graft survival in a clinically relevant non-human primate model. Peripheral blood Tregs were isolated and expanded using artificial antigen presenting cells. Immunosuppression was comprised of tapered tacrolimus and CTLA4 immunoglobulin, in five animals each without or with Treg infusions. Escalating Treg doses were administered 6, 10, 13, 16, 20, 23, 27 and 30 days after transplant. Infused Tregs were monitored for Treg signature, anti-apoptotic (Bcl-2) and proliferation (Ki67) marker expression. Treg infusions prolonged median graft survival time significantly from 35 to 70 days. Treg marker (Ki67 and Bcl-2) expression by infused Tregs diminished after their infusion but remained comparable to that of circulating native Tregs. No major changes in circulating donor-reactive T cell responses or total Treg percentages, or in graft-infiltrating T cell subsets were observed with Treg infusion. However, Treg infusion was associated with significant increases in CD163 expression by circulating HLA-DR+ myeloid cells and elevated levels of circulating soluble CD163. Further, graft-infiltrating CD163+ cells were increased with Treg infusion. Thus, multiple Treg infusions were associated with M2-like myeloid cell enhancement that may mediate immunomodulatory, anti-inflammatory and graft reparative effects.
Distinct association between chronic Epstein-Barr virus infection and T cell compartments from pediatric heart, kidney, and liver transplant recipients
Abstract: View Article – Chronic Epstein-Barr virus (EBV) infection after pediatric organ transplantation (Tx) accounts for significant morbidity and mortality. The risk of complications, such as posttransplant lymphoproliferative disorders, in high viral load (HVL) carriers is the highest in heart Tx recipients. However, the immunologic signatures of such a risk have been insufficiently defined. Here, we assessed the phenotypic, functional, and transcriptomic profiles of peripheral blood CD8+/CD4+ T cells, including EBV-specific T cells, in 77 pediatric heart, kidney, and liver Tx recipients and established the relationship between memory differentiation and progression toward exhaustion. Unlike kidney and liver HVL carriers, heart HVL carriers displayed distinct CD8+ T cells with (1) up-regulation of interleukin-21R, (2) decreased naive phenotype and altered memory differentiation, (3) accumulation of terminally exhausted (TEX PD-1+T-bet−Eomes+) and decrease of functional precursors of exhausted (TPEX PD-1intT-bet+) effector subsets, and (4) transcriptomic signatures supporting the phenotypic changes. In addition, CD4+ T cells from heart HVL carriers displayed similar changes in naive and memory subsets, elevated Th1 follicular helper cells, and plasma interleukin-21, suggesting an alternative inflammatory mechanism that governs T cell responses in heart Tx recipients. These results may explain the different incidences of EBV complications and may help improve the risk stratification and clinical management of different types of Tx recipients.
Tissue-resident memory T cell maintenance during antigen persistence requires both cognate antigen and interleukin-15
Abstract: View Article – Our understanding of tissue-resident memory T (TRM) cell biology has been largely developed from acute infection models in which antigen is cleared and sterilizing immunity is achieved. Less is known about TRM cells in the context of chronic antigen persistence and inflammation. We investigated factors that underlie TRM maintenance in a kidney transplantation model in which TRM cells drive rejection. In contrast to acute infection, we found that TRM cells declined markedly in the absence of cognate antigen, antigen presentation, or antigen sensing by the T cells. Depletion of graft-infiltrating dendritic cells or interruption of antigen presentation after TRM cells were established was sufficient to disrupt TRM maintenance and reduce allograft pathology. Likewise, removal of IL-15 transpresentation or of the IL-15 receptor on T cells during TRM maintenance led to a decline in TRM cells, and IL-15 receptor blockade prevented chronic rejection. Therefore, antigen and IL-15 presented by dendritic cells play nonredundant key roles in CD8 TRM cell maintenance in settings of antigen persistence and inflammation. These findings provide insights that could lead to improved treatment of chronic transplant rejection and autoimmunity.
Tracking kidney transplant fitness: An implantable bioelectronic device detects the early signs of kidney transplant rejection in rats
Graft-versus-host disease is locally maintained in target tissues by resident progenitor-like T cells
Abstract: View Article – In allogeneic hematopoietic stem cell transplantation, donor αβ T cells attack recipient tissues, causing graft-versus-host disease (GVHD), a major cause of morbidity and mortality. A central question has been how GVHD is sustained despite T cell exhaustion from chronic antigen stimulation. The current model for GVHD holds that disease is maintained through the continued recruitment of alloreactive effectors from blood into affected tissues. Here, we show, using multiple approaches including parabiosis of mice with GVHD, that GVHD is instead primarily maintained locally within diseased tissues. By tracking 1,203 alloreactive T cell clones, we fitted a mathematical model predicting that within each tissue a small number of progenitor T cells maintain a larger effector pool. Consistent with this, we identified a tissue-resident TCF-1+ subpopulation that preferentially engrafted, expanded, and differentiated into effectors upon adoptive transfer. These results suggest that therapies targeting affected tissues and progenitor T cells within them would be effective.
Early Effect of the Circular Model of Kidney Allocation in the United States
Abstract: View Article – In March 2021, the United States implemented a new kidney allocation system (KAS250) for deceased donor kidney transplantation (DDKT), which eliminated the donation service area-based allocation and replaced it with a system on the basis of distance from donor hospital to transplant center within/outside a radius of 250 nautical miles. The effect of this policy on kidney discards and logistics is unknown.
Innate allorecognition in transplantation: Ancient mechanisms with modern impact
Author: Zeping Gui, Mouhamad Al Mousawwy, Steven M. Sanders, Khodor I. Abou-Daya
Abstract: View Article – Through the effective targeting of the adaptive immune system, solid organ transplantation became a life-saving therapy for organ failure. However, beyond 1 y of transplantation, there is little improvement in transplant outcomes. The adaptive immune response requires the activation of the innate immune system. There are no modalities for the specific targeting of the innate immune system involvement in transplant rejection. However, the recent discovery of innate allorecognition and innate immune memory presents novel targets in transplantation that will increase our understanding of organ rejection and might aid in improving transplant outcomes. In this review, we look at the latest developments in the study of innate allorecognition and innate immune memory in transplantation.