Insight into Noninvasive Radiological Modalities to Detect Heart Transplant Rejection

Purpose Patients with end-stage heart failure who remain symptomatic even with exemplary medical and device therapy are treated with heart transplantation. Multitudes of endeavor have been contrived during the last decennium in the field of noninvasive tests to rule out heart transplant rejection (HTR). In spite of having supportive literature, noninvasive imaging techniques lack acceptable documentation of clinical robustness, and endomyocardial biopsy (EMB) still remains the gold standard. The aim of this review is to shed light on the existing noninvasive radiological modalities to detect rejection among heart transplant recipients. Methods A comprehensive search was conducted for this review article on the basis of literature available including scientific databases of PubMed, Embase, and Google Scholar, using keywords of “Heart transplantation,” “Acute allograft rejection,” “Arrhythmias,” “Echocardiography,” “Speckle tracking echocardiography,” and “Cardiac magnetic resonance imaging” from inception until September 2020. Results After preliminary screening of the databases, details regarding existent noninvasive radiological modalities to detect HTR were gathered and compiled in this review article. Currently, deformation imaging using speckle tracking and T2 time using cardiac magnetic resonance imaging can serve as screening tools based on which further invasive investigations can be planned. Standardization of blood-based and imaging modalities as screening and possible diagnostic tools for rejection would have obvious clinical and financial benefits in the care of growing number of post heart transplant recipients in our country. Conclusion Diagnosis of allograft rejection in heart transplant recipients through noninvasive techniques is demanding. To unravel the potential of noninvasive radiological modalities that can serve as a standard-of-care test, a prospective multicentric study randomizing noninvasive modality as first strategy versus current EMB-based gold standard of care is the need of the hour.

Tilting the Balance: Therapeutic Prospects of CD83 as a Checkpoint Molecule Controlling Resolution of Inflammation

Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) protein has emerged as an interesting potential candidate for such a “pro-resolution” therapy. This molecule occurs in a membrane-bound and a soluble isoform (mCD83 and sCD83, respectively), both of which are involved in resolution of inflammation. Originally described as a maturation marker on dendritic cells (DCs), mCD83 is also expressed by activated B and T cells as well as regulatory T cells (Tregs) and controls turnover of MHC II molecules in the thymus, and thereby positive selection of CD4+ T cells. Additionally, it serves to confine overshooting (auto-)immune responses. Consequently, animals with a conditional deletion of CD83 in DCs or regulatory T cells suffer from impaired resolution of inflammation. Pro-resolving effects of sCD83 became evident in pre-clinical autoimmune and transplantation models, where application of sCD83 reduced disease symptoms and enhanced allograft survival, respectively. Here, we summarize recent advances regarding CD83-mediated resolution of inflammatory responses, its binding partners as well as induced signaling pathways, and emphasize its therapeutic potential for future clinical trials.

Induction of Donor-Specific Immune Hypo-Responsiveness Across Major Histocompatibility Complex Barriers in Murine Models of Solid Organ Transplant: Repurposing Extracorporeal Photochemotherapy

Recipients of solid organ transplantation (SOT) rely on life-long immunosuppression (IS), which is associated with significant side effects. Extracorporeal photochemotherapy (ECP) is a safe, existing cellular therapy used to treat transplant rejection by modulating the recipient’s own blood cells. We sought to induce donor-specific hypo-responsiveness of SOT recipients by infusing ECP-treated donor leukocytes prior to transplant. To this end, we utilized major histocompatibility complex (MHC) mismatched rodent models of allogeneic cardiac, liver, and kidney transplantation to test this novel strategy. Leukocytes isolated from donor-matched spleens for ECP treatment (ECP-DL) were infused into transplant recipients seven days prior to SOT. Pre-transplant infusion of ECP-DL without additional IS was associated with prolonged graft survival in all models. This innovative approach promoted the production of tolerogenic dendritic cells and regulatory T-cells with subsequent inhibition of T-cell priming and differentiation, along with a significant reduction of donor-specific T-cells in the spleen and grafts of treated animals. This new application of donor-type ECP-treated leukocytes provides insight into the mechanisms behind ECP-induced immunoregulation and holds significant promise in the prevention of graft rejection and reduction in need of global immune suppressive therapy in patients following SOT.

Efficient In Vitro Generation of IL-22-Secreting ILC3 From CD34+ Hematopoietic Progenitors in a Human Mesenchymal Stem Cell Niche

Innate lymphoid cells (ILCs) and in particular ILC3s have been described to be vital for mucosal barrier functions and homeostasis within the gastrointestinal (GI) tract. Importantly, IL-22-secreting ILC3 have been implicated in the control of inflammatory bowel disease (IBD) and were shown to reduce the incidence of graft-versus-host disease (GvHD) as well as the risk of transplant rejection. Unfortunately, IL-22-secreting ILC3 are primarily located in mucosal tissues and are not found within the circulation, making access to them in humans challenging. On this account, there is a growing desire for clinically applicable protocols for in vitro generation of effector ILC3. Here, we present an approach for faithful generation of functionally competent human ILC3s from cord blood-derived CD34+ hematopoietic progenitors on layers of human mesenchymal stem cells (MSCs) generated in good manufacturing practice (GMP) quality. The in vitro-generated ILC3s phenotypically, functionally, and transcriptionally resemble bona fide tissue ILC3 with high expression of the transcription factors (TF) RorγT, AHR, and ID2, as well as the surface receptors CD117, CD56, and NKp44. Importantly, the majority of ILC3 belonged to the desired effector subtype with high IL-22 and low IL-17 production. The protocol thus combines the advantages of avoiding xenogeneic components, which were necessary in previous protocols, with a high propensity for generation of IL-22-producing ILC3. The present approach is suitable for the generation of large amounts of ILC3 in an all-human system, which could facilitate development of clinical strategies for ILC3-based therapy in inflammatory diseases and cancer.

Application of Graphene in Tissue Engineering of the Nervous System

Graphene is the thinnest two-dimensional (2D), only one carbon atom thick, but one of the strongest biomaterials. Due to its unique structure, it has many unique properties used in tissue engineering of the nervous system, such as high strength, flexibility, adequate softness, electrical conductivity, antibacterial effect, and the ability to penetrate the blood–brain barrier (BBB). Graphene is also characterized by the possibility of modifications that allow for even wider application and adaptation to cell cultures of specific cells and tissues, both in vitro and in vivo. Moreover, by using the patient's own cells for cell culture, it will be possible to produce tissues and organs that can be re-transplanted without transplant rejection, the negative effects of taking immunosuppressive drugs, and waiting for an appropriate organ donor.