Genetic Background and Allorecognition Phenotype in Hydractinia symbiolongicarpus

The Hydractinia allorecognition complex (ARC) was initially identified as a single chromosomal interval using inbred and congenic lines. The production of defined lines necessarily homogenizes genetic background and thus may be expected to obscure the effects of unlinked allorecognition loci should they exist. Here, we report the results of crosses in which inbred lines were out-crossed to wild-type animals in an attempt to identify dominant, codominant, or incompletely dominant modifiers of allorecognition. A claim for the existence of modifiers unlinked to ARC was rejected for three different genetic backgrounds. Estimates of the genetic map distance of ARC in two wild-type haplotypes differed markedly from one another and from that measured in congenic lines. These results suggest that additional allodeterminants exist in the Hydractinia ARC

CD45 ligation expands Tregs by promoting interactions with DCs

Regulatory T cells (Tregs), which express CD4 and FOXP3, are critical for modulating the immune response and promoting immune tolerance. Consequently, methods to expand Tregs for therapeutic use are of great interest. While transfer of Tregs after massive ex vivo expansion can be achieved, in vivo expansion of Tregs would be more practical. Here, we demonstrate that targeting the CD45 tyrosine phosphatase with a tolerogenic anti-CD45RB mAb acutely increases Treg numbers in WT mice, even in absence of exogenous antigen. Treg expansion occurred through substantial augmentation of homeostatic proliferation in the preexisting Treg population. Moreover, anti-CD45RB specifically increased Treg proliferation in response to cognate antigen. Compared with conventional T cells, Tregs differentially regulate their conjugation with DCs. Therefore, we determined whether CD45 ligation could alter interactions between Tregs and DCs. Live imaging showed that CD45 ligation specifically reduced Treg motility in an integrin-dependent manner, resulting in enhanced interactions between Tregs and DCs in vivo. Increased conjugate formation, in turn, augmented nuclear translocation of nuclear factor of activated T cells (NFAT) and Treg proliferation. Together, these results demonstrate that Treg peripheral homeostasis can be specifically modulated in vivo to promote Treg expansion and tolerance by increasing conjugation between Tregs and DCs

The unfinished legacy of liver transplantation: Emphasis on immunology

Liver transplantation radically changed the philosophy of hepatology practice, enriched multiple areas of basic science, and had pervasive ripple effects in law, public policy, ethics, and theology. Why organ engraftment was feasible remained enigmatic, however, until the discovery in 1992 of donor leukocyte microchimerism in long-surviving liver, and other kinds of organ recipients. Following this discovery, the leukocyte chimerism-associated mechanisms were elucidated that directly linked organ and bone marrow transplantation and eventually clarified the relationship of transplantation immunology to the immunology of infections, neoplasms, and autoimmune disorders. We describe here how the initially controversial paradigm shift mandated revisions of cherished dogmas. With the fresh insight, the reasons for numerous inexplicable phenomena of transplantation either became obvious or have become susceptible to discriminate experimental testing. The therapeutic implications of the "new immunology" in hepatology and in other medical disciplines, have only begun to be explored. Apart from immunology, physiologic investigations of liver transplantation have resulted in the discovery of growth factors (beginning with insulin) that are involved in the regulation of liver size, ultrastructure, function, and the capacity for regeneration. Such studies have partially explained functional and hormonal relationships of different abdominal organs, and ultimately they led to the cure or palliation by liver transplantation of more than 2 dozen hepatic-based inborn errors of metabolism. Liver transplantation should not be viewed as a purely technologic achievement, but rather as a searchlight whose beams have penetrated the murky mist of the past, and continue to potentially illuminate the future. Copyright © 2006 by the American Association for the Study of Liver Diseases

Ignorance is bliss

In an elegant transgenic mouse model, Bolinger and colleagues provide evidence that endothelial cells expressing a nonself minor histocompatibility antigen neither activate nor tolerize CD8+ T cells. Instead, the antigen is ignored by the immune system. The findings are relevant to both graft-versus-host disease and the rejection of solid-organ transplants

Origin and Biology of the Allogeneic Response

The recognition by the immune system of nonself determinants on cells, tissues, or organs transplanted between genetically disparate members of the same species can lead to a potent allogeneic response that is responsible for rejection. We review here fundamental concepts that underlie the origins and biology of allorecognition in the mammalian immune system. We examine why and how T cells are alloreactive and discuss emerging evidence of allorecognition by innate immune cells. The nature of T cells (naïve vs. memory) and the alloantigen presentation pathways (direct, indirect, and semidirect) that initiate the allogeneic response are outlined

Origin and biology of the allogeneic response

The recognition by the immune system of nonself determinants on cells, tissues, or organs transplanted between genetically disparate members of the same species can lead to a potent allogeneic response that is responsible for rejection. We review here fundamental concepts that underlie the origins and biology of allorecognition in the mammalian immune system. We examine why and how T cells are alloreactive and discuss emerging evidence of allorecognition by innate immune cells. The nature of T cells (naïve vs. memory) and the alloantigen presentation pathways (direct, indirect, and semidirect) that initiate the allogeneic response are outlined

Memory T Cell Migration

Immunological memory is a key feature of adaptive immunity. It provides the organism with long-lived and robust protection against infection. In organ transplantation, memory T cells pose a significant threat by causing allograft rejection that is generally resistant to immunosuppressive therapy. Therefore, a more thorough understanding of memory T cell biology is needed to improve the survival of transplanted organs without compromising the host’s ability to fight infections. This review will focus on the mechanisms by which memory T cells migrate to the site where their target antigen is present, with particular emphasis on their migration to transplanted organs. First, we will define the known subsets of memory T cells (central, effector, and tissue resident) and their circulation patterns. Second, we will review the cellular and molecular mechanisms by which memory T cells migrate to inflamed and non-inflamed tissues and highlight the emerging paradigm of antigen-driven, trans-endothelial migration. Third, we will discuss the relevance of this knowledge to organ transplantation and to the prevention or treatment of allograft rejection