Review
Towards cytoprotection in the peritransplant period

https://doi.org/10.1016/j.smim.2011.07.006Get rights and content

Abstract

As a consequence of ischemia–reperfusion injury of whole organ transplants and hypoxia–anoxia of cell transplants, transplantation unavoidably triggers adverse, cytodestructive inflammation within the allograft. Interventions that dampen adverse inflammation may limit the extent and duration of this injury, and preserve tissue function. Moreover, these interventions should create a milieu that guides many donor-activated T cells into a tissue-protective phenotype, thus promoting graft acceptance or even tolerance. Hence, it is useful, maybe crucial, to identify the measures that minimize deleterious consequences of acute and chronic inflammation upon allograft. Several therapies that inhibit activity of certain proinflammatory cytokines or expression of tissue “danger signals”, while sustaining or potentially enhancing the expression of tissue-intrinsic anti-inflammatory and cytoprotective genes, are awaiting clinical trials or are already approved for the treatment of immuno-inflammatory disorders. If applied in the peritransplant period, such cytoprotective regimens may increase the pool of donor organs suitable for transplantation, reduce the overall requirements for maintenance immunosuppression and perhaps foster transplant tolerance.

Highlights

► Inflammation adversely influences short-term and long-term graft outcomes. ► Immunosuppressants used in transplantation do not effectively treat inflammation. ► Therapies blocking inflammation attenuate graft injury and foster transplant tolerance.

Introduction

Transplantation of solid organs and tissues leads to an abrupt inflammatory reaction, independent of the degree of genetic mismatch between the donor and the recipient, due to surgical trauma, anoxia–hypoxia and the ischemia–reperfusion injury [1], [2], [3], [4], [5]. In fact, immune and inflammatory genes expressed in syngeneic and allogeneic transplants but not normal tissues do not markedly differ until after several days post-transplant, a period required by donor-reactive T cells to home into the allograft [6], [7], [8], [9]. The texture of the milieu in which T cells recognize alloantigen largely determines the type of their response; T-effector, aimed at graft destruction or T-regulatory, aimed at graft protection [10], [11], [12]. Ischemia and reperfusion-incited IL-1β, TNFα and IL-6-rich inflammation, if left untreated, fosters commitment of activated T cells into graft-destructive phenotypes, while blocking their commitment into graft-protective phenotypes, thus creating a major barrier to transplant tolerance [13], [14], [15], [16], [17], [18]. Hence, we and others believe that modulation of the microenvironment in which T-cell activation occurs may prove to be a key strategy to foster transplant tolerance [19], [20], [21], [22], [23], [24]. It is therefore reasonable to posit that targeting tissue destructive type immune and inflammatory cell pathways therapeutically in the immediate perioperative period should prove beneficial by creating an immunoregulatory T-cell friendly milieu prior to T-cell activation by alloantigens. Currently used immunosuppressants, are largely directed at the adaptive immune response blocking T-cell activation and most, do not efficiently modulate adverse inflammation [25], [26]. Adverse graft inflammation, thus left essentially untreated, increases the incidence of delayed graft function and acute rejection as well as later risk of graft loss due to the chronic rejection and fibrotic tissue changes [27], [28], [29]. In current clinical practice, corticosteroids, agents that cause broad suppression of both anti-inflammatory and proinflammatory cytokines with significant side effects are the only anti-inflammatory intervention used in transplantation [30], [31], [32], [33]. We sense a need to introduce new therapies to specifically target components of the adverse inflammation and perhaps promote tissue-intrinsic or immune-mediated cytoprotection (Fig. 1). Several agents, such as antagonists of proinflammatory cytokines, inhibitors of serine proteases or inhalational anti-inflammatory gaseous molecules convey substantial cytoprotection in pre-clinical transplant models. A potential increase in tissue resistance to hypoxia, such as seen with pharmacological stabilization of cytoprotective transcription factor HIF1α, or cell death reduction following anti-apoptotic gene transfers (Bcl-2), may be especially beneficial to non-vascularized transplants such as pancreatic islets or hepatocytes that undergo a significant period of hypoxia before their revascularization occurs in the recipient. However, these strategies, if used alone will not likely suffice to achieve a long-term allograft survival in the absence of adaptive immune system targeting agents. These agents are absolutely essential to tackle unusually large pool of recipient T cells able to respond to alloantigens, as well as memory T cells in pre-sensitized recipients. However, the use of cytoprotective agents in the peritransplant period could serve to preserve tissue function and limit the tissue-inflammatory reaction triggered by the ischemia and reperfusion injury, thus creating a milieu permissive to the induction and maintenance of transplant tolerance.

Section snippets

Promoting transplant tolerance with cytokine inhibitors

Several proinflammatory cytokines, including IL-1β, IL-6, and TNFα are produced by intragraft innate immune cells in a response to the anoxia–hypoxia and ischemia and reperfusion injury. A variety of tissue-injurious mechanisms trigger cytokine production, such as intracellular ATP depletion and caspase activation during prolonged hypoxia (IL-1β), generation of free oxygen radicals (TNFα), or Toll-like receptor stimulation by endogenous “danger signals” such as subcellular tissue components

Protecting transplants with acute phase proteins

Acute phase proteins, synthesized in hepatocytes and secreted into plasma, are very sensitive markers of acute and chronic inflammation, as their production is stimulated by various proinflammatory cytokines (IL-1α, IL-1β, IL-6, TNFα) [51], [52]. Two acute phase proteins with a serine protease inhibitor (“serpin”) activity, alpha 1-antitrypsin (α1-AT) and C1-esterase inhibitor, have long been used as protein replacement therapies in patients affected by mutations of their genes; the α1-AT gene

Enhancing graft-intrinsic cytoprotection

Perioperative ischemic injury of organ transplants is a strong trigger of cytoprotective tissue response, aimed at preserving cell survival and tissue function [3], [13]. Cytoprotective genes (heme oxygenase 1, A20, bcl-2, bcl-xl), transcription factors (HIF-1α) as well as certain metabolites (carbon monoxide, bilirubin, adenosine) play a role. Inducing or enhancing their expression with targeted therapies before T-cell mediated graft injury ensues may serve to favorably modify intragraft

Conclusion

The combination of hypoxic and immunologic injury that occurs in organ transplantation creates significant therapeutic challenges. Currently used anti-rejection therapies, although effective in targeting adaptive immunity, do not modulate early innate immune activation occurring due to the ischemia–reperfusion injury, and do not promote tissue-intrinsic cytoprotective response. However, it is now widely accepted, that the ischemia and reperfusion injury-incited inflammation adversely affects

Acknowledgment

Dr. Maria Koulmanda has received grant support from NIH (PPG U19 DK080652, PO1 AI073748 and PO1 AI041521) and JDRF (4-2004-368 and 1-2007-524).

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