Distinct Pro-Inflammatory Species-Specific Transcriptional Changes in Human T Cells Following Pig Xenogeneic Stimulation.

Conventional T cell-directed immunosuppression is the mainstay of standard-of-care therapy to prevent graft rejection in clinical organ transplantation. However, it remains ineffective in preventing experimental and clinical organ xenograft rejection. Here, we explored the impact of allogeneic versus xenogeneic antigen stimulation on human T cell responses and gene profile.

The transformative potential of artificial intelligence in solid organ transplantation.

Solid organ transplantation confronts numerous challenges ranging from donor organ shortage to post-transplant complications. Here, we provide an overview of the latest attempts to address some of these challenges using artificial intelligence (AI). We delve into the application of machine learning in pretransplant evaluation, predicting transplant rejection, and post-operative patient outcomes.

Lymphotoxin β receptor and tertiary lymphoid organs shape acute and chronic allograft rejection.

Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLOs) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLOs regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin αβ/lymphotoxin β receptor (LTαβ/LTβR) pathway, which is essential for TLO formation, to define the role of TLOs in transplantation.

Innate Allorecognition in Transplantation: Ancient Mechanisms With Modern Impact.

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.

Tissue-resident memory T cell maintenance during antigen persistence requires both cognate antigen and interleukin-15.

Our understanding of tissue-resident memory T (T) cell biology has been largely developed from acute infection models in which antigen is cleared and sterilizing immunity is achieved. Less is known about T cells in the context of chronic antigen persistence and inflammation. We investigated factors that underlie T maintenance in a kidney transplantation model in which T cells drive rejection.

Transitional B cell cytokines risk stratify early borderline rejection after renal transplantation.

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 shortened allograft survival would allow for timely targeted therapeutic intervention aimed at improving outcomes. 851/1187 patients transplanted between 2013-18 underwent early biopsy (0-4 mos).

Activated-memory T cells influence naïve T cell fate: a noncytotoxic function of human CD8 T cells.

T cells are endowed with the capacity to sense their environment including other T cells around them. They do so to set their numbers and activation thresholds. This form of regulation has been well-studied within a given T cell population - i.

Innate allorecognition in transplantation.

Successful allogeneic transplantation has been made possible by suppressing activation of the adaptive immune system. Current immunosuppressive therapy prevents rejection by targeting T and B cells. Despite this effective treatment, it is the innate immune system, which includes dendritic cells, monocytes, natural killer cells, that is responsible for the initiation of the adaptive immune response.

Resident memory T cells form during persistent antigen exposure leading to allograft rejection.

Tissue-resident memory T cells (T) contained at sites of previous infection provide local protection against reinfection. Whether they form and function in organ transplants where cognate antigen persists is unclear. This is a key question in transplantation as T cells are detected long term in allografts, but it is not known whether they are exhausted or are functional memory T cells.

Innate Allorecognition and Memory in Transplantation.

Over the past few decades, we have witnessed a decline in the rates of acute rejection without significant improvement in chronic rejection. Current treatment strategies principally target the adaptive immune response and not the innate response. Therefore, better understanding of innate immunity in transplantation and how to target it is highly desirable.

PIRs mediate innate myeloid cell memory to nonself MHC molecules.

Immunological memory specific to previously encountered antigens is a cardinal feature of adaptive lymphoid cells. However, it is unknown whether innate myeloid cells retain memory of prior antigenic stimulation and respond to it more vigorously on subsequent encounters. In this work, we show that murine monocytes and macrophages acquire memory specific to major histocompatibility complex I (MHC-I) antigens, and we identify A-type paired immunoglobulin-like receptors (PIR-As) as the MHC-I receptors necessary for the memory response.

Cross-dressed dendritic cells sustain effector T cell responses in islet and kidney allografts.

Activation of host T cells that mediate allograft rejection is a 2-step process. The first occurs in secondary lymphoid organs where T cells encounter alloantigens presented by host DCs and differentiate to effectors. Antigen presentation at these sites occurs principally via transfer of intact, donor MHC-peptide complexes from graft cells to host DCs (cross-dressing) or by uptake and processing of donor antigens into allopeptides bound to self-MHC molecules (indirect presentation).

Donor SIRPα polymorphism modulates the innate immune response to allogeneic grafts.

Mice devoid of T, B, and natural killer (NK) cells distinguish between self and allogeneic nonself despite the absence of an adaptive immune system. When challenged with an allograft, they mount an innate response characterized by accumulation of mature, monocyte-derived dendritic cells (DCs) that produce interleukin-12 and present antigen to T cells. However, the molecular mechanisms by which the innate immune system detects allogeneic nonself to generate these DCs are not known.

CD8+ Effector T Cell Migration to Pancreatic Islet Grafts Is Dependent on Cognate Antigen Presentation by Donor Graft Cells.

Pancreatic islet transplantation is a promising therapy for diabetes, but acute rejection of the islets by host effector T cells has hindered clinical application. In this study, we addressed the mechanisms of CD8(+) effector T cell migration to islet grafts because interrupting this step is key to preventing rejection. We found that effector T cell migration to revascularized islet transplants in mice is dependent on non-self Ag recognition rather than signaling via Gαi-coupled chemokine receptors.

Effects of rosiglitazone (PPAR γ agonist) on the myocardium in non-hypertensive diabetic rats (PPAR γ).

Background: There is ongoing controversy regarding the safety of rosiglitazone and its effects on the myocardium, in some cases causing severe cardiac pathology and even in some instances mortality. In this study we aimed at examining the effects of pharmacologic doses of rosiglitazone on cardiomyocytes in diabetic non-cardiac rats receiving sub-optimal doses of insulin.

Methods: Animals were distributed into six groups: normal, diabetic, and diabetic receiving insulin, each subdivided into a control group and an experimental group receiving pharmacologic doses of rosiglitazone.