Where Are All the Clinical Trials for Chronic Rejection?

Chronic rejection is arguably the main obstacle to long-term graft survival. Yet, clinical trials focusing on this condition are disappointingly scarce. Significant advances in treating chronic rejection cannot happen if there is no conduit for testing novel therapies.

Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance.

Stem cells reside in specialized microenvironments, termed niches, at several different locations in tissues. The differential functions of heterogeneous stem cells and niches are important given the increasing clinical applications of stem-cell transplantation and immunotherapy. Whether hierarchical structures among stem cells at distinct niches exist and further control aspects of immune tolerance is unknown.

A brief report on biomarkers of cellular senescence associated with liver frailty and length of stay in liver transplantation.

The proportion of older individuals needing liver transplantation is growing, resulting in an increasingly frail patient population. Frailty constitutes a constellation of cognitive and physical symptoms associated with aging and increases the risk of morbidity and mortality. Senescence is a programmed cell fate in response to stress implicated in causing frailty, age-related diseases, and aging itself.

Vascular endothelial cells derived from transgene-free pig induced pluripotent stem cells for vascular tissue engineering.

Induced pluripotent stem cells (iPSCs) hold great promise for the treatment of cardiovascular diseases through cell-based therapies, but these therapies require extensive preclinical testing that is best done in species-in-species experiments. Pigs are a good large animal model for these tests due to the similarity of their cardiovascular system to humans. However, a lack of adequate pig iPSCs (piPSCs) that are analogous to human iPSCs has greatly limited the potential usefulness of this model system.

Peritumoral Venous Vessels: Autobahn and Portal for T Cells to Melanoma Brain Metastasis.

Melanoma brain metastasis is associated with high morbidity and mortality and remains a major clinical challenge. Despite recent successes with combination immune checkpoint inhibitors in the treatment of affected patients, the mechanistic underpinnings of T-cell entry and response to these drugs in brain metastasis are poorly understood. Using real-time intravital microscopy, Messmer and colleagues identified peritumoral venous vessels (PVV) as critical sites for T-cell entry into brain metastases, a process accelerated by immune checkpoint inhibitor treatment.

Clones reactive to apoptotic cells and specific chemical adducts are prevalent among human thymic B cells.

Introduction: Thymus resident B cells were described more than 40 years ago. In early human life, these cells are found predominantly in the medulla and overwhelmingly display an unswitched IgM+ phenotype. The reactivity of thymic IgM B cells, however, is still unclear.

The 3 I's of immunity and aging: immunosenescence, inflammaging, and immune resilience.

As we age, our immune system's ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases.

Frailty and pre-frailty associated with long-term diminished physical performance and quality of life in breast cancer and hematopoietic cell transplant survivors.

Physical frailty as a sign of accelerated aging is not well characterized in breast cancer (BC) and hematopoietic cell transplant (HCT) survivors and its correlation with outcomes and quality of life (QOL) is not defined. We conducted a prospective study to determine the prevalence of frailty in adult BC and HCT survivors, examine its impact on QOL, and determine its association with , a molecular biomarker for biological aging. The study included 59 BC and 65 HCT survivors.

Unveiling Common Transcriptomic Features between Melanoma Brain Metastases and Neurodegenerative Diseases.

Melanoma represents a critical clinical challenge owing to its unfavorable outcomes. This type of skin cancer exhibits unique adaptability to the brain microenvironment, but its underlying molecular mechanisms are poorly understood. Recent findings have suggested that melanoma brain metastases may share biological processes similar to those found in various neurodegenerative diseases.

Neoadjuvant androgen deprivation therapy with or without Fc-enhanced non-fucosylated anti-CTLA-4 (BMS-986218) in high risk localized prostate cancer: a randomized phase 1 trial.

Men with high-risk localized prostate cancer exhibit high rates of post-surgical recurrence. In these patients, androgen deprivation therapy (ADT) is immunomodulatory, however increased infiltration of regulatory T cells (Tregs) may limit the antitumor immune effects of ADT. We designed a neoadjuvant clinical trial to test whether BMS-986218 - a next-generation non-fucosylated anti-CTLA-4 antibody engineered for enhanced antibody-dependent cellular cytotoxicity or phagocytosis (ADCC/P) - depletes intratumoral Tregs and augments the response to ADT.

An Imaging-Based Assay to Measure the Location of PD-1 at the Immune Synapse for Testing the Binding Efficacy of Anti-PD-1 and Anti-PD-L1 Antibodies.

PD-1 is an immune checkpoint on T cells. Antibodies to PD-1 or its ligand PD-L1 are gaining popularity as a leading immunotherapy approach. In the US, 40% of all cancer patients will be treated with anti-PD-1 or anti-PD-L1 antibodies but, unfortunately, only 30% will respond, and many will develop immune-related adverse events.

Role of chemokine receptors in transplant rejection and graft-versus-host disease.

Organ transplantation increases life expectancy and improves the quality of life of patients experiencing specific conditions such as terminal organ failure. Despite matching efforts between donor and recipient, immune activation can interfere with allograft survival after transplantation if immunosuppression is not used. With both innate and adaptive responses, this is a complicated immunological process.

Role of chemokine receptors in gastrointestinal mucosa.

Chemokine receptors are essential for the immune response in the oral and gut mucosa. The gastrointestinal mucosa is characterized by the presence of immune populations because it is susceptible to inflammatory and infectious diseases, necessitating immune surveillance. Chemokine receptors are expressed on immune cells and play a role in gastrointestinal tissue-homing, although other non-immune cells also express them for various biological functions.

Chemokine receptors in primary and secondary lymphoid tissues.

Chemokine receptors are a complex superfamily of surface G protein-coupled receptors present mostly in leukocytes. In this chapter, we review the presence and functions of chemokine receptors in the immune cells of the primary and secondary lymphoid organs. Those include bone marrow, thymus, spleen, lymph nodes, and Peyer's patches as the main components of the gut-associated lymphoid tissue.

Harnessing cellular therapeutics for type 1 diabetes mellitus: progress, challenges, and the road ahead.

Type 1 diabetes mellitus (T1DM) is a growing global health concern that affects approximately 8.5 million individuals worldwide. T1DM is characterized by an autoimmune destruction of pancreatic β cells, leading to a disruption in glucose homeostasis.

Differences in Acute Graft-Versus-Host Disease (GVHD) Severity and Its Outcomes Between Black and White Patients.

Acute graft-versus-host disease (GVHD) is a significant complication following hematopoietic stem cell transplantation (HCT). Although recent advancements in GVHD prophylaxis have resulted in successful HCT across HLA barriers and expanded access to HCT for racial minorities, less is known about how race affects the severity and outcomes of acute GVHD. This study examines differences in the clinical course of acute GVHD and the prognostic value of GVHD biomarkers for Black and White recipients.

An engineered human cardiac tissue model reveals contributions of systemic lupus erythematosus autoantibodies to myocardial injury.

Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease that affects multiple organs, including the heart. The mechanisms of myocardial injury in SLE remain poorly understood. In this study, we engineered human cardiac tissues and cultured them with IgG from patients with SLE, with and without myocardial involvement.

Infectious Disease Prophylaxis During and After Immunosuppressive Therapy.

Immune-mediated renal diseases are a diverse group of disorders caused by antibody, complement, or cell-mediated autosensitization. Although these diseases predispose to infection on their own, a growing array of traditional and newer, more targeted immunosuppressant medications are used to treat these diseases. By understanding their mechanisms of action and the infections associated with suppression of each arm of the immune system, nephrologists can better anticipate these risks and effectively prevent and recognize opportunistic infections.

Single-Cell Profiling of Sarcomas from Archival Tissue Reveals Programs Associated with Resistance to Immune Checkpoint Blockade.

Purpose: Sarcoma encompasses a diverse group of cancers that are typically resistant to current therapies, including immune checkpoint blockade (ICB), and underlying mechanisms are poorly understood. The contexture of sarcomas limits generation of high-quality data using cutting-edge molecular profiling methods, such as single-cell RNA-sequencing, thus hampering progress in understanding these understudied cancers.

Experimental Design: Here, we demonstrate feasibility of producing multimodal single-cell genomics and whole-genome sequencing data from frozen tissues, profiling 75,716 cell transcriptomes of five undifferentiated pleomorphic sarcoma and three intimal sarcoma samples, including paired specimens from two patients treated with ICB.

Exclusion of PD-1 from the immune synapse: A novel strategy to modulate T cell function.

Targeting immune checkpoint receptors on T cells is a common cancer treatment strategy. Frequently, this is accomplished through antibodies targeting the ligand of inhibitory co-receptors. Blocking the immune checkpoint PD-1 binding to its ligands PD-L1 and PD-L2 prevents downstream signaling and enhances anti-tumor T cell responses.

Update on Maintenance Immunosuppression in Intestinal Transplantation.

Outcomes in intestinal transplantation remain hampered by higher rates of rejection than any other solid organs. However, maintenance immunosuppression regimens have largely remained unchanged despite advances in therapies for induction and treatment of rejection and graft-versus-host disease. Recently, there have been a small number of new maintenance therapies attempted, and older agents have been used in new ways to achieve better outcomes.