Foxp3 is a transcription factor that is essential for the normal development of regulatory T cells (Tregs). In the absence of microRNAs (miRNAs), Foxp3+ Tregs develop but fail to maintain immune homeostasis, leading to a scurfy-like disease. Global analysis of the network of genes regulated by Foxp3 has identified the miRNA miR-155, which is highly expressed in Tregs, as a direct target of Foxp3. In this study we report that miR-155-deficient mice have reduced numbers of Tregs, both in the thymus and periphery, due to impaired development. However, we found no evidence for defective suppressor activity of miR-155-deficient Tregs, either in vitro or in vivo. Our results indicate that miR-155 contributes to Treg development, but that additional miRNAs control Treg function.
CD4+CD25+Foxp3+ regulatory T cells (Tregs) contribute to the maintenance of peripheral tolerance by inhibiting the expansion and function of conventional T cells. Treg development and homeostasis are regulated by the Ag receptor, costimulatory receptors such as CD28 and CTLA-4, and cytokines such as IL-2, IL-10, and TGF-β. Here we show that the proportions of Tregs in the spleen and lymph nodes of mice with inactive p110δ PI3K (p110δD910A/D910A) are reduced despite enhanced Treg selection in the thymus. p110δD910A/D910A CD4+CD25+Foxp3+ Tregs showed attenuated suppressor function in vitro and failed to secrete IL-10. In adoptive transfer experiments, p110δD910A/D910A T cells failed to protect against experimental colitis. The identification of p110δ as an intracellular signaling protein that regulates the activity of CD4+CD25+Foxp3+ Tregs may facilitate the further elucidation of the molecular mechanisms responsible for Treg-mediated suppression.
Immune‐mediated hemolytic anemia (IMHA) causes severe anemia in dogs and is associated with considerable morbidity and mortality. Treatment with various immunosuppressive and antithrombotic drugs has been described anecdotally and in previous studies, but little consensus exists among veterinarians as to the optimal regimen to employ and maintain after diagnosis of the disease. To address this inconsistency and provide evidence‐based guidelines for treatment of IMHA in dogs, we identified and extracted data from studies published in the veterinary literature. We developed a novel tool for evaluation of evidence quality, using it to assess study design, diagnostic criteria, explanation of treatment regimens, and validity of statistical methods. In combination with our clinical experience and comparable guidelines for humans afflicted with autoimmune hemolytic anemia, we used the conclusions of this process to make a set of clinical recommendations regarding treatment of IMHA in dogs, which we refined subsequently by conducting several iterations of Delphi review. Additionally, we considered emerging treatments for IMHA in dogs and highlighted areas deserving of future research. Comments were solicited from several professional bodies to maximize clinical applicability before the recommendations were submitted for publication. The resulting document is intended to provide clinical guidelines for management of IMHA in dogs. These guidelines should be implemented pragmatically, with consideration of animal, owner, and veterinary factors that may vary among cases.
Immune‐mediated hemolytic anemia (IMHA) is an important cause of morbidity and mortality in dogs. IMHA also occurs in cats, although less commonly. IMHA is considered secondary when it can be attributed to an underlying disease, and as primary (idiopathic) if no cause is found. Eliminating diseases that cause IMHA may attenuate or stop immune‐mediated erythrocyte destruction, and adverse consequences of long‐term immunosuppressive treatment can be avoided. Infections, cancer, drugs, vaccines, and inflammatory processes may be underlying causes of IMHA. Evidence for these comorbidities has not been systematically evaluated, rendering evidence‐based decisions difficult. We identified and extracted data from studies published in the veterinary literature and developed a novel tool for evaluation of evidence quality, using it to assess study design, diagnostic criteria for IMHA, comorbidities, and causality. Succinct evidence summary statements were written, along with screening recommendations. Statements were refined by conducting 3 iterations of Delphi review with panel and task force members. Commentary was solicited from several professional bodies to maximize clinical applicability before the recommendations were submitted. The resulting document is intended to provide clinical guidelines for diagnosis of, and underlying disease screening for, IMHA in dogs and cats. These should be implemented with consideration of animal, owner, and geographical factors.
Neonatal tolerance of alloantigens was described in mice nearly half a century ago, but unfortunately, the translation of these early findings into the clinical arena proved to be much more challenging than was first anticipated. However, the past decade has seen considerable progress in our understanding of the mechanisms that contribute to transplantation tolerance in experimental models. This review outlines our current understanding of the mechanisms of allograft tolerance, emphasizing the complementary roles of deletion and regulation of alloreactive T cells.
Objective. To investigate the hypothesis that loss of suppression mediated by peripheral CD4؉,CD25؉ regulatory T cells is a hallmark of systemic lupus erythematosus (SLE).
Sepsis, the systemic inflammatory response to infection, represents the major cause of death in critically ill veterinary patients. Whereas important advances in our understanding of the pathophysiology of this syndrome have been made, much remains to be elucidated. There is general agreement on the key interaction between pathogen‐associated molecular patterns and cells of the innate immune system, and the amplification of the host response generated by pro‐inflammatory cytokines. More recently, the concept of immunoparalysis in sepsis has also been advanced, together with an increasing recognition of the interplay between regulatory T cells and the innate immune response. However, the heterogeneous nature of this syndrome and the difficulty of modeling it in vitro or in vivo has both frustrated the advancement of new therapies and emphasized the continuing importance of patient‐based clinical research in this area of human and veterinary medicine.
In recent years, mesenchymal stromal cells (MSCs) and regulatory T cells (Tregs) have both garnered significant interest from immunologists worldwide, not least because of the potential application of both cell types in the treatment of many chronic inflammatory and autoimmune diseases. Although both MSCs and Tregs can be considered immunosuppressive in their own right, the induction of Tregs by activated MSCs is now a well-publicised phenomenon; however, only recently have the mechanisms involved in this induction started to become clear. Indeed, it is becoming increasingly apparent that there exists a complex interplay between the two lineages leading to this potent inhibition of the host immune response. Cell contact, soluble mediators-including prostaglandin E(2) and transforming growth factor β-and indirect induction via manipulation of other antigen-presenting cells all appear to have vital roles in the interactions between MSCs and Tregs. Much still remains to be discovered before we have a full understanding of this important aspect of the immune response, but there have already been a multitude of clinical trials suggesting that MSC/Treg therapies could offer significant benefits in the treatment of both autoimmune disease and graft versus host disease. Although these therapies are still in their infancy, the synergy between MSCs and Tregs will undoubtedly yield future breakthroughs in the treatment of many debilitating conditions and usher in a new wave of targeted, cell-based therapeutics.
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