Prope tolerance: the future of organ transplantation—from the laboratory to the clinic

Ry, Calne

doi:10.1097/01.tp.0000117776.14277.03

Cited by 48 publications

(14 citation statements)

References 31 publications

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“…Lack of thymic chimerism under CsA protocol prevents development of tolerogenic T cells among newly developing lymphocytes, and a low dose of CsA maintenance therapy is necessary to prevent alloreactivity and to maintain allograft survival. However, a low, nontoxic dose of CsA maintenance protocol, used in VCA, is permissive for “prope” tolerance induction as reported in solid organ transplantations [62]. The pharmacologic result is an altered immune response, inhibiting the activation process of T cells by IL-2 production and by downregulating surface costimulatory molecule expression on rodent and human dendritic cells [63, 64].…”

Section: Immunosuppressive Versus Immunodepletive Protocols and Chmentioning

confidence: 99%

Chimerism-Based Experimental Models for Tolerance Induction in Vascularized Composite Allografts: Cleveland Clinic Research Experience

Siemionow

Klimczak

2013

Clinical and Developmental Immunology

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The preclinical experimental models of vascularized composite allografts (VCAs) have been rapidly developed for the assessment of immunomodulatory protocols for clinical application. Recently, researchers have focused on immunomodulatory protocols which overcome the immunologic barrier between the allogeneic donor and recipient and may lead to tolerance induction. In order to test the feasibility of chimerism induction, experimental VCAs have been performed in different models including rodents, large animals, and nonhuman primates. These models differ in the complexity of transplanted tissue and in their responses to immunomodulatory protocols. In most applications, VCA contains multiple-tissue components; however, each individual component of CTA possesses unique immunologic characteristics that ultimately contribute to the chimerism induction and successful outcome of the VCA. Heterogenic character and complexity of tissue components in different VCA models determine the quality and robustness of donor-specific chimerism. As introduced in experimental studies, variable immunomodulatory options have been studied to achieve tolerance to VCA in rodents and large animal models allowing for widespread application in clinic. In this paper, based on our own experience, we have analyzed the current knowledge of tolerance-inducing strategies via chimerism induction in VCA experimental models in the context of immunomodulatory protocols and VCA complexity and their relevance and applicability to clinical practice.

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Section: Immunosuppressive Versus Immunodepletive Protocols and Chmentioning

confidence: 99%

Chimerism-Based Experimental Models for Tolerance Induction in Vascularized Composite Allografts: Cleveland Clinic Research Experience

Siemionow

Klimczak

2013

Clinical and Developmental Immunology

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“…One of the problems is that, by definition, one can only know that tolerance is achieved by retrospection—tolerance is the absence of rejection. Sir Roy Calne uses the term “prope” (near) tolerance to get over the semantics—prope tolerance is the best we can achieve in humans 52. The vast majority of renal transplant patients will reject their transplant if they stop all immunosuppression, although a few do not.…”

Section: Investigation Of Graft Dysfunctionmentioning

confidence: 99%

Modern renal transplantation: present challenges and future prospects

Galliford

Game

2009

Postgraduate Medical Journal

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Renal transplantation offers patients with end stage renal failure improved survival and quality of life compared with dialysis. Although more transplants are being performed in the UK and elsewhere, the size of the renal transplant waiting list is increasing at a faster rate. Live donor transplantation between antibody compatible and incompatible pairs is one of the short term solutions to this; it may also be a sensible long term strategy since it affords better outcomes. Following successful transplantation, balancing the chronic and often deleterious effects of immunosuppression with chronic immune damage poses the key clinical challenge for transplant physicians today. Research efforts worldwide are focused towards immunological tolerance of transplanted organs with two main questions: first, how can we induce tolerance; and second, how can we test that it is operational? Immunosuppressive protocols vary greatly between transplant units, which may be reflected in differing patient and allograft survival.

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“…In contrast with transplantation tolerance, operational tolerance does not necessarily mean complete unresponsiveness of the recipient immune system toward the donor cell (split tolerance), but rather refers to the lack of a destructive immune response toward the graft despite the presence of generalized immune competence 5. (3) Prope tolerance, as proposed by Calne, describes a state of “almost tolerance” in patients who maintain normal allograft function and histology under minimal IS, usually a monotherapy calcineurin inhibition with infratherapeutic blood levels 7–9. (4) Graft acceptance defines the common situation in which a transplant recipient has a normal immunosuppressive load, with absence of immune injury toward the graft; this condition is typically observed in the subgroup of recipients without acute rejection episode in the early and middle‐term posttransplant period, under routine immunoprophylaxis, usually with combination of drugs including calcineurin inhibition.…”

Section: Allogenic Tolerance: Terminology and Generic Mechanismsmentioning

confidence: 99%

The immunological monitoring of alloreactive responses in liver transplant recipients: A review

et al. 2006

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The aim of this work is to review the current knowledge in the field of immunological monitoring of allogenic responsiveness in clinical liver transplantation. When compared to other solid-organ transplants, liver allografts are considered as immunologically privileged, and, accordingly, constitute a favorable setting to develop experimental as well as clinical strategies for minimization of immunosuppression and even induction of operational tolerance. The validation of simple, reliable, noninvasive assays exploring antidonor alloreactivity will constitute a crucial step toward implementing such approaches in the clinic. In contrast to research in rodents claiming the development of donor-specific tolerance in case of graft survivals of over 100 days without immunosuppression, it is impractical to confirm tolerance induction in this way in humans. Since the first human liver transplant (LT) some 52 years ago, the vast majority of hepatic allograft recipients have remained under life-long maintenance immunosuppression (IS). Despite the dramatic improvement of early graft survival, late graft losses due to chronic rejection as well as the morbidity and mortality secondary to long-term IS remain major concerns in this field.1,2 Induction of tolerance to the transplant would prevent these complications, and clinical LT probably constitutes an ideal setting to develop such strategies, considering its immunologically privileged status when compared to other types of allografts.3 However, despite the observation that tolerance has been relatively "easy" to induce in rodent models, the translation of these researches in humans has not yet been shown to reproducibly induce IS-free tolerant state in transplant recipients. In experimental models, tolerance can be assessed by graft survival beyond 100 days without IS, and by absence of rejection of a donor strain skin transplant; such an approach is of course impractical in humans, and the only currently available method to ascertain tolerance in a given patient is the ability to progressively withdraw all IS with preservation of graft function and histology. Unfortunately, although a small number of grafts are not rejected after removal of all medications used for the maintenance IS, trials involving the deliberate withdrawal of immunosuppressive drugs according to a protocol do not suggest that it is safe to do so for most patients: Such trials are associated with the inherent risk to induce acute or even chronic rejection with the need for higher levels of IS when compared to the stable situation before attempting at IS withdrawal.

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Prope tolerance: the future of organ transplantation—from the laboratory to the clinic

Cited by 48 publications

References 31 publications

Chimerism-Based Experimental Models for Tolerance Induction in Vascularized Composite Allografts: Cleveland Clinic Research Experience

Chimerism-Based Experimental Models for Tolerance Induction in Vascularized Composite Allografts: Cleveland Clinic Research Experience

Modern renal transplantation: present challenges and future prospects

The immunological monitoring of alloreactive responses in liver transplant recipients: A review

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