Department of Medicine, Transplantation Institute and Institute of Immunology, Mount Sinai School of Medicine, New York, New York
Correspondence: Dr. Peter S. Heeger, Mount Sinai School of Medicine, Annenberg Box 1243, One Gustave L. Levy Plaza, New York, NY 10025. Phone: 212-241-6324; Fax: 212-987-0389; E-mail: peter.heeger{at}mssm.edu
The field of transplantation has come a long way since the firstsuccessful kidney transplant performed by Murray and colleaguesin 1954. Kidney, heart, lung, and liver transplantation, amongother organs, is now routine, and short-term (1 yr) outcomeshave steadily improved to rates of >90 to 95% graft survival(http://www.unos.org). Despite these successes, the major shortfallof our current therapy, which requires potent immunosuppressionfor life, is that long-term graft survival rates are unacceptable.1Fifty percent of kidney transplants are lost by the 10- to 13-yrmark, and survival of heart and lung transplants is significantlyworse. The clinical, emotional, and economic consequences ofkidney graft failure to the patient, including reinstitutionof dialysis, retransplantation, and death, are enormous. Becausenewer therapies have not had an impact on long-term outcomes,many clinicians and scientists believe that the only way toimprove significantly these less-than-optimal long-term resultsis to eliminate immunosuppression while somehow training therecipient's immune system to be nonresponsive to the donor organ—thatis, to induce immunologic tolerance.
The initial description and "proof of principle" that acquiredimmune tolerance could be achieved came from the now classicstudies by Sir Peter Medawar and collegues,2 for which he wasawarded the Nobel Prize in 1960. Since then, we have learneda vast amount regarding underlying mechanisms of tolerance andhow to induce immune tolerance successfully in animals. Thislarge body of work has shown that central and peripheral deletionof autoreactive T and B cells, anergy (unresponsiveness), ignorance,and active regulation/suppression are the predominant mechanismsthrough which an organism's immune system differentiates nondangerousself-tissues from foreign invaders that must be destroyed. Applyingthese concepts to animal models of transplantation, numerousresearch groups have shown that it is possible to exploit thesame mechanisms to achieve indefinite graft survival associatedwith an absence of pathologic immune reactivity to the donororgan while maintaining an otherwise intact immune system—trueimmunologic tolerance. The accomplishments have included approachesthat use "re-educating" the immune system (immunoablation andbone marrow transplantation), blocking co-stimulatory moleculesthat are involved in activation and differentiation of pathogenicT and B cells, and inducing active immune regulation. Translationof the successes seen in small animal models to human transplantrecipients has been difficult, but we now realize that transplanttolerance can be achieved in humans, and we are beginning tounderstand the barriers that need to be overcome to facilitateits induction. The goal of this month's Frontiers in Nephrologyis to provide an update on this topic, including an analysisof clinical transplant tolerance in humans, as well as severalarticles that discuss newly recognized mechanisms of and barriersto achieving the tolerant state.
In the initial clinical contribution, Girlanda and Kirk3 reviewthe current state of the art of human transplantation toleranceand offer several take-home messages. First, operational tolerance,prolonged graft survival without allograft injury in the absenceof immunosuppression, does indeed occur spontaneously in humans,albeit rarely (<1% of transplants). Ongoing work throughthe National Institutes of Health–funded Immune ToleranceNetwork, among other sources, is studying spontaneously tolerantkidney transplant recipients, and emerging data are beginningto provide some clues as to underlying mechanisms. The articleemphasizes that although tolerance is often recognized becauseof nonadherence to medical regimens, the vast majority of patientswho stop taking their medications develop rejection and graftloss. Girlanda and Kirk also outline our current understandingof tolerance mechanism. They review the current experience intolerance induction protocols in humans, including nonmyeloablativebone marrow transplantation and co-stimulatory blockade andprovide potential explanations for why it is more difficultto induce tolerance in humans versus animals. Lastly, the reviewemphasizes the important concept that tolerance is a dynamicprocess influenced by the host's environmental exposures, thusnecessitating the development and implementation of novel approachesto define and detect the tolerant state.
One such environmental force is the constant exposure to infectiousorganisms that the immune system must effectively respond toand that could have an impact on the tenuous nature of acquiredtolerance. The article by Selin and Brehm4 addresses this issuethrough discussing the complexities of cross-reactive/heterologousT cell immunity. The authors outline the data supporting theconcept that immune responses that are induced to one infectiousorganism often cross-react with, and subsequently influence,immunity that is reactive to antigens from a different pathogen.Depending on the specific effect of the initial insult on theimmune repertoire, the result can aid the host in eradicatinganother infection or occasionally can prevent the host's immunesystem from responding appropriately to a different, secondinsult. The authors then discuss the highly relevant conceptthan an antiviral immune response can cross-react with, andthereby have an impact on, the immune response to a transplantedorgan, potentially accelerating rejection and preventing toleranceinduction. The constant exposure to viral antigens is one ofmany differences between humans and animals in controlled laboratoryenvironments (in which tolerance is routinely induced), providingone explanation for why tolerance may be more difficult to achievein humans.
This theme is explored in further depth by Valujskikh and Li5in their contribution on T cell memory as a barrier to transplantation.In practice, T cell memory results from exposure to pathogens,immunizations, blood transfusions, pregnancies, and previoustransplants, among other stimuli. Immunologic memory evolvedto respond rapidly and effectively to infectious organisms alreadyencountered by the host, thereby limiting the clinical impactof the secondary infection. When compared with naïve Tcells, memory T cells are more frequent, have higher functionalavidity, and can respond faster to their specific cognate antigen.Although these features are clearly protective in the contextof preventing re-infection, such features could have a negativeimpact on transplant outcome. It turns out that human immunerepertoires often contain alloreactive memory T cells, likelyas a result of previous environmental exposures that cross-reactwith alloantigens. With this as a background, Valujskikh andLi then outline the data that T cell memory functions as a barrierto transplant tolerance, explain how memory cells prevent tolerance,and describe how new therapeutic approaches specifically targetingmemory T cells may be effective in circumventing this importantbarrier.
In the final contribution of the series, Bielke and Gill6 describea recently discovered and unanticipated novel paradigm in transplanttolerance: That natural killer (NK) cells can be pro-tolerogenic.NK cells are considered a component of the innate immune system.They express germline-encoded activating and inhibitory receptorsand are thought to respond rapidly after an immune stimulusby killing infected cells and shaping the subsequent proinflammatoryadaptive immune repertoire. Despite these known effects andan established role in preventing bone marrow engraftment, ithas been difficult to delineate a clear function for NK cellsas mediators of solid-organ transplant injury (limited evidencesuggests that NK cells contribute to chronic allograft failure).The surprise outlined by Beilke and Gill is that NK cells canbe essential mediators of transplant tolerance; that is, tolerancecannot be induced in their absence. These authors outline thedata to support this conclusion and provide insight into howthe NK cell may function to facilitate the tolerant state. Anunderstanding of this novel paradigm has the potential to providenew targets for inducing and maintaining tolerance in humans.
Despite more than 50 yr of progress in the clinical care oftransplant patients and in the science underlying transplanttolerance, we know that allograft tolerance is achievable inhumans but that many barriers prevent routine induction andmaintenance of the allograft-tolerant state. It is hoped thatthe recent findings described in this Frontiers in Nephrologywill spawn new research and will help guide the design of novelapproaches to implement, maintain, and monitor transplant tolerancein humans.
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Girlanda R, Kirk AD: Frontiers in nephrology: Immune tolerance to allografts in humans.
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Selin LK, Brehm MA: Frontiers in nephrology: Heterologous immunity, T cell cross-reactivity, and alloreactivity.
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Valujskikh A, Li XC: Frontiers in nephrology: T cell memory as a barrier to transplant tolerance.
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Bielke JN, Gill RG: Frontiers in nephrology: The varied faces of natural killer cells in transplantation—Contributions to both allograft immunity and tolerance.
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Introduction
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