Old game, new players: Linking classical theories to new trends in transplant immunology

Abstract

The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the setting of disorders such as autoimmunity and transplant rejection. In light of the latter, although research has long uncovered main concepts of allogeneic recognition, immune rejection is still the main obstacle to long-term graft survival. Therefore, in order to define effective therapies that prolong graft viability, it is essential that we understand the underlying mediators and mechanisms that participate in transplant rejection. This multifaceted process is characterized by diverse cellular and humoral participants with innate and adaptive functions that can determine the type of rejection or promote graft acceptance. Although a number of mediators of graft recognition have been described in traditional immunology, recent studies indicate that defining rigid roles for certain immune cells and factors may be more complicated than originally conceived. Current research has also targeted specific cells and drugs that regulate immune activation and induce tolerance. This review will give a broad view of the most recent understanding of the allogeneic inflammatory/tolerogenic response and current insights into cellular and drug therapies that modulate immune activation that may prove to be useful in the induction of tolerance in the clinical setting.

Mycophenolic acid pharmacogenomics in kidney transplantation

“…MPA is a reversible inhibitor of inosine-5´-monophosphate dehydrogenase (IMPDH), an important enzyme involved in the de novo synthesis of guanosine nucleotides, which are essential for the proliferation of T and B cells [1,2] . Consequently, guanosine nucleotide depletion by MPA prevents DNA replication, leads to repression of both cell-and humoral-mediated immunity and induces tolerance to allograft in kidney transplantation [1,3,4] . IMPDH activity results from the expression of two isoforms, IMPDH type I and type II, which are encoded by IMPDH1 and IMPDH2, respectively [2] .…”

Papel da Sirtuina 1 na ativação e diferenciação das células T CD4>sup<+>/sup< em um modelo murino de obesidade e transplante

“…Three types of rejection have been described: hyperacute, acute and chronic (Chalasani et al, 2004;Moreau et al, 2013). Hyperacute rejection is characterized by the preexistence of antibodies against donor antigens (IgG and IgM, usually previously formed), activating the complement system or innate immune system cells causing endothelial damage, leading to vascular thrombotic occlusion of the graft, within minutes or hours, soon after anastomosis between the graft vessels and the recipient's circulatory system (da Silva et al, 2017). Acute rejection, however, is due to effector mechanisms of CD4 + and CD8 + T lymphocytes against donor-specific antigen, causing damage to the graft parenchyma and blood vessels in weeks or months after transplantation.…”

“…Acute rejection, however, is due to effector mechanisms of CD4 + and CD8 + T lymphocytes against donor-specific antigen, causing damage to the graft parenchyma and blood vessels in weeks or months after transplantation. Similarly, chronic rejection is related to vascular occlusion caused by proliferation of intimal smooth muscle cells and collagen deposits in the parenchyma that result from the accumulation of cytokines and other factors released by graft-reactive T cells and phagocytes (da Silva et al, 2017;Wood & Goto, 2012).…”

Papel da sirtuína 1 no fenótipo e função de células dendríticas no contexto do transplante em animais obesos

“…Apesar de melhores drogas imunossupressoras terem surgido nos últimos anos (HALLORAN, 2004), os pacientes ainda são totalmente dependentes dessas drogas pelo resto de suas vidas e o custo do tratamento pós-operatório é, na sua grande maioria, exorbitante. Embora atualmente a combinação das moléculas de MHC, entre doador e receptor, seja considerado essencial para o sucesso de um transplante (TASAKI, 1990), somente depois de alguns anos de estudos moleculares e celulares foi comprovado que as moléculas de MHC têm um papel fundamental durante a sinapse imunológica entre células apresentadoras de antígenos (do inglês, antigen presenting cells, APC), principalmente relacionado a DCs, e linfócitos T (SILVA et al, 2017).…”

“…Por outro lado, a apresentação indireta, envolve a captura e o processamento de antígenos do doador e apresentação em moléculas de MHC de classe I e classe II pelas APCs do receptor para as células T do receptor. Mais recentemente, foi descrito a apresentação semi-indireta, a qual está relacionada com a interação entre células T e APCs que levam ao intercâmbio de complexos MHC: peptídeos pelo contato direto entre células (NANKIVELL;ALEXANDER, 2010;SILVA et al, 2017). Por fim, em qualquer tipo de apresentação antigênica, os mecanismos efetores que provocam a rejeição são comandados majoritariamente por subtipos de linfócitos T CD4+ (WOOD; GOTO, 2012).…”