Abstract
Over the last decades, our understanding of adaptive immune responses to solid organ transplantation increased considerably and allowed development of immunosuppressive drugs targeting key alloreactive T cells mechanism. As a result, rates of acute rejection dropped and short-term graft survival improved significantly. However, long-term outcomes are still disappointing. Recently, increasing evidence supports that innate immune responses plays roles in allograft rejection and represents a valuable target to further improve long-term allograft survival. Innate immune cells are activated by molecules with stereotypical motifs produced during injury (i.e., damage-associated molecular patterns, DAMPS) or infection (i.e., pathogen-associated molecular patterns, PAMPs). Activated innate immune cells can exert direct pro- and anti-inflammatory effects, while also priming adaptive immune responses. These cells are activated after transplantation by multiple stimuli, including ischemia-reperfusion injury, rejection, and infections. Data from animal models of graft rejection, show that inhibition of innate immunity promotes development of tolerance. Therefore, understanding mechanisms of innate immunity is important to improve graft outcomes. This review discusses effects of currently used immunosuppressive agents on innate immune responses in kidney transplantation.
Highlights
INTRODUCTIONStrategies to prevent allograft rejection have focused purely on preventing adaptive immunity
For many years, strategies to prevent allograft rejection have focused purely on preventing adaptive immunity
We will review relevant literature regarding the impact of the main immunosuppressive agents employed in the maintenance phase of kidney transplantation on innate immune responses
Summary
Strategies to prevent allograft rejection have focused purely on preventing adaptive immunity. Immunosuppressive Therapy and Innate Immunity (i.e., pathogen-associated molecular patterns, PAMPs) initiate a variety of inflammatory events, including diapedesis, inflammatory cytokine production, and cell death [8]. These pattern recognition receptor (PRR)-mediated inflammatory responses are necessary for microbial clearance. Occurring post-transplant and resulting from release of endogenous PRR ligands, so-called “sterile inflammation,” they can lead to severe and often irreversible graft tissue damage and fibrosis [8, 9] These phenomena provide a link to adaptive immune responses through induced costimulatory molecule expression and cytokine-mediated “help.”. We will review relevant literature regarding the impact of the main immunosuppressive agents employed in the maintenance phase of kidney transplantation (calcineurin inhibitors, mycophenolate mofetil/mycophenolic acid, corticosteroids, and mTOR inhibitors) on innate immune responses
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