Results and Problems in Cell Differentiation最新文献

While lung transplantation is a life-saving treatment option for patients with end-stage lung diseases, its long-term outcome is hampered by exceedingly high rates of chronic rejection, manifesting as chronic lung allograft dysfunction (CLAD). It has long been recognized that exposure of the lung to the external environment via the airways, coupled with its rich immune microenvironment, makes the lung uniquely susceptible to heightened alloimmunity. Extensive immunosuppressive drugs do not provide effective control of the process of chronic rejection, and so, in recent years, investigators have turned their attention toward the identification of underlying cellular mechanisms that are either inherently resistant to or evolve to escape these medications. In this review, we explore recent advances in identifying the cellular mediators of chronic lung allograft rejection, with a focus on the myeloid-T cell immune axis, which will require targeted therapeutic approaches in the future to prevent irreversible allograft fibrosis.

Chronic liver allograft rejection (CR) remains a significant cause of late graft dysfunction and failure despite advances in surgical techniques and immunosuppression. This chapter reviews the current understanding of CR, integrating diagnostic histopathological findings, atypical histological patterns of late rejection that are frequently associated with CR, and emerging diagnostic tools. CR is driven by overlapping T cell-mediated and antibody-mediated mechanisms, leading to progressive bile duct loss, vascular injury, and structural alterations. Diagnostic histopathological criteria include interlobular bile duct atrophy or loss, foam cell obliterative arteriopathy, and portal/periportal, perisinusoidal, and perivenular fibrosis. Chronic antibody-mediated rejection (cAMR) and mixed phenotypes exhibit additional vascular and sinusoidal injury, often with subtle biochemical changes. Structural sequelae such as nodular regenerative hyperplasia and variable parenchymal fibrosis underscore the heterogeneity of late graft injury. This chapter also examines late-onset rejection phenotypes, i.e., plasma cell-rich rejection, idiopathic post-transplant hepatitis, and isolated central perivenulitis and their potential to progress to chronic rejection. Future directions emphasize the integration of molecular diagnostics, digital pathology, and noninvasive biomarkers, such as donor-specific antibodies, liver stiffness measurement, and donor-derived cell-free DNA (dd-cfDNA), to complement or replace protocol biopsies, to guide personalized immunosuppression, and to enable earlier intervention. Advances in regenerative medicine and antifibrotic therapies have the potential to alter the natural history of CR, shifting toward precision medicine approaches that may extend long-term graft survival after liver transplantation.

Antibody-mediated rejection (AMR) is now recognized as the primary cause of the decline of functional integrity and ultimately, graft failure in kidney transplants. Evolving understanding of effectors responsible for B-cell activation and plasma cell biology has led to the informed design of new therapeutics. Currently, several novel agents with varying mechanisms of action have emerged. These include imlifidase, FcRn inhibitors, anti-cytokine (IL-6/IL-6R) therapies, and plasma cell-directed therapies, especially anti-CD38s. As our understanding of critical effector pathways responsible for ARM grows, we now know that no single agent can control all facets of antibody generation and injury. The future of antibody-directed therapeutics will require protocols consisting of multiple agents positioned in a logical sequence to rapidly and durably remove pathogenic DSAs and block their re-emergence.

There is no cure for chronic rejection of transplanted organs. Macrophages are heavily involved in chronic rejection. Macrophages' movement into the graft depends on the actin cytoskeleton and its regulators the GTPase RhoA and its effector ROCK kinase. In this chapter, we describe how the interference with macrophage RhoA/ROCK pathway disrupts macrophage actin cytoskeleton, impairing their functions and migration to the allograft, and preventing the development of chronic rejection, and how such interference can be applied to clinical therapies.

The vascular endothelium serves as an indispensable border for the interaction and exchange of molecules and cells between the blood flow and tissues. Upon transplantation, the endothelium of the allograft is the first to come into contact with the recipient's blood and becomes injured by alloreactive and nonalloreactive stimuli. Repetitive injuries lead to severe damage of the endothelium resulting in the development of chronic rejection over time.The objective of this chapter is to highlight recent insights into the most relevant endothelial molecules, mediators, and pathways crucial in the evolvement of chronic organ rejection. We also discuss new avenues of drugs that can diminish or prevent damage to the endothelium leading to an otherwise irreversible development of chronic organ rejection.

Chronic rejection of allografts appears mechanistically distinct from acute antibody-mediated and or acute cell-mediated rejection. Histological features point to roles for alloantibody and lymphocytic infiltrates, and allograft vasculopathy is a common feature in chronic rejection of several different solid organs. Vasculopathy, in turn, can cause late graft failure due to chronic ischemia, parenchymal cell loss, and replacement fibrosis. Molecular analyses implicate graft vascular endothelial cells in this process. Here, we review evidence favoring a hypothesis linking alloantibody and complement to induction of endothelial cell surface expression and trans-presentation of IL-15 as a critical signal that enhances lymphocyte activation during antigen-mediated recruitment of alloreactive T cells. These T cells trans-migrate into the intima and secrete interferon-γ, which acts both on vascular smooth muscle cells within the arterial wall to stimulate their proliferation, resulting in vasculopathy, and back on the endothelial cells to provide positive feedback for this sequence of events.

Chronic rejection remains a significant challenge in solid organ transplantation, contributing to graft dysfunction and eventual failure despite advances in immunosuppressive therapies. Computational modeling has emerged as a powerful tool for understanding chronic rejection mechanisms, enhancing diagnostic precision, and identifying novel therapeutic targets. This chapter explores various computational approaches, including artificial intelligence, machine learning, ordinary differential equations, partial differential equations, agent-based models, and gene network analysis applied to solid organ transplantation: kidney, liver, heart, and lung. While computational models offer numerous advantages, including cost-effectiveness and the ability to integrate multi-omics data, challenges remain in terms of data quality, standardization, and clinical validation. Bridging these gaps will require comprehensive longitudinal studies and the development of hybrid models that combine diverse computational techniques. Emerging technologies such as single-cell transcriptomics and spatial genomics hold promise for enhancing predictive accuracy and understanding cellular heterogeneity. As computational methods evolve, their integration with experimental research will be essential for developing precision medicine strategies to improve long-term graft survival.

Today, there have been spectacular advances in surgical techniques, organ preservation for transplantation, optimal and efficient donor and recipient selection, more efficient diagnosis of transplant complications, and major progress in pharmacological immunosuppression procedures. In this regard, survival rates after transplantation of various organs have been gaining ground, particularly in the case of lung transplants, whose average survival rate is lower than other types of transplants. In this regard, it is important to detect acute and subclinical clinical rejection, as well as chronic allograft rejection. This is especially important in heart and lung transplants. In the latter type of transplant, and due to the chronic dysfunction of the lung allograft, it is key to detect rejection early and promptly, as it can affect up to half of the transplant patient population. Therefore, effective diagnostic tools are needed to visualize the level of allograft damage using genomic methods such as those that measure donor-derived cell-free DNA (dd-cfDNA). The plasma concentration of dd-cfDNA increases after graft injury or infection. Our team has experience quantifying this parameter in allograft injury progression, and our experience and comparison with the published literature will be presented in the following sections, discussing validated and non-validated results.

The naked mole-rat (Heterocephalus glaber) is a fascinating model organism which challenges conventional paradigms in evolutionary developmental biology. As one of the two known eusocial mammals with a reproductive hierarchy akin to social insects, the naked mole-rat presents an exceptional system for studying the interplay between social structure, environmental adaptation, and developmental plasticity. This chapter explores how the species' unique reproductive strategies-including lifelong fertility, postnatal oogenesis, and social suppression of reproduction-reshape our understanding of mammalian reproductive aging. The queen, the sole breeding female within a colony, maintains an exceptionally large ovarian reserve throughout life, defying the prevailing dogma of a fixed oocyte pool and progressive depletion. Unlike other mammals, germ cells in the naked mole-rat continue to proliferate postnatally, offering unprecedented insights into the regulation of ovarian function and reproductive longevity. Additionally, the integration of genomic, epigenetic, and neuroendocrine mechanisms underlying eusociality provides a rare perspective on how developmental processes can be shaped by cooperative behaviors and environmental constraints. By situating these traits within an evo-devo framework, this chapter underscores the naked mole-rat's potential to advance research in several fields such as aging, reproductive biology, and the evolution of complex social systems.

Intensive research for 50 years did not find a way to predict the faith of organ transplants after successful transplantation. Current immunosuppressive regiments reduce kidney transplant acute rejection episodes to 6-11% for the first year, but 49% of them develop chronic allograft nephropathy in 5 years. Similarly, heart transplants have 8% acute rejection episodes in the first year and 50% develop cardiac vasculopathy in 5 years. Multiple cytokines regulate acute cellular T-cell-mediated rejection (TCMR) and acute antibody-mediated rejection (AMR), and both mechanisms contribute to chronic allograft rejection. In addition to common γ chain (cγ) cytokines [interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21], other cytokines [IL-1, IL-6, IL-10, interferon-α, (IFN)α, INFβ, INFγ, tumor necrosis factor α, TNFα; tumor growth factor β, TGFβ] are all extensively involved in the regulation of acute and chronic allograft rejections. Interestingly, the same cytokines also regulate functions of normal cells and tissues. To induce transplant tolerance, it is necessary to maintain physiological cytokine levels as well as boost the function of T regulatory T (Treg) cells producing IL-10, IL-35, and TGFβ. This chapter emphasizes the necessity of maintaining a balance by cytokines to divert them from the inflammation path producing chronic rejection to normal function support combined with Treg-dominated transplantation tolerance.