Transplantation tolerance in pediatric recipients: Lessons and challenges

Tinckam, Kathryn; Sayegh, Mohamed H.

doi:10.1111/j.1399-3046.2004.00220.x

Cited by 9 publications

(6 citation statements)

References 123 publications

(137 reference statements)

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“…25 A second skin graft was therefore transplanted onto each of the following treatment groups 5 to 7 weeks after placement of the first graft: (1) anti-CD154 alone; (2) anti-␣␤ TCR alone; or (3) both mAbs. Mice without mAb treatment at the primary skin graft served as controls.…”

Section: Secondary Skin Graft Survival and Donor-specific Ab Generationmentioning

confidence: 99%

Costimulatory blockade of CD154-CD40 in combination with T-cell lymphodepletion results in prevention of allogeneic sensitization

Yan

Huang

et al. 2008

Blood

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Sensitization is a critical unresolved challenge in transplantation. We show for the first time that blockade of CD154 alone or combined with T-cell depletion prevents sensitization. Allogeneic skin grafts were rejected by recipients treated with anti-␣␤ T-cell receptor (TCR), anti-CD154, anti-OX40L, or anti-inducible costimulatory pathway (ICOS) mAb alone with a kinetic similar to untreated recipients. However, the production of anti-donor MHC antibody was prevented in mice treated with anti-CD154 mAb only, suggesting a specific role for the CD154-CD40 pathway in B-cell activation. The impairment of T celldependent B-cell responses by blocking CD154 occurs through inhibiting activation of T and B cells and secretion of IFN-␥ and IL-10. Combined treatment with both anti-CD154 and anti-␣␤ TCR abrogated antidonor antibody production and resulted in prolonged skin graft survival, suggesting the induction of both T-and B-cell tolerance with prevention of allogeneic sensitization. In addition, we show that the tolerance induced by combined treatment was nondeletional. Moreover, these sensitization-preventive strategies promote bone marrow engraftment in recipients previously exposed to donor alloantigen. These findings may be clinically relevant to prevent allosensitization with minimal toxicity and point to humoral immunity as playing a dominant role in alloreactivity in sensitized recipients. IntroductionSensitization of patients to major histocompatibility complex (MHC) antigens is among the most critical challenges in clinical transplantation. [1][2][3] Patients with preformed antibodies have higher rejection rates and inferior outcomes for bone marrow transplantation (BMT) and organ transplantation. Most patients with sickle cell disease and thalassemia who are candidates for BMT are sensitized due to chronic transfusion therapy. 4 Similarly, in solid organ transplantation, allorejection mediated by preformed antibodies has recently been recognized as a major cause of graft loss in sensitized patients. Although 20% of candidates for renal transplantation are sensitized, they receive less than 3% of available organs. 1 The increased use of ventricular assist devices as a bridge to cardiac transplantation also sensitizes these candidates to MHC alloantigens prior to transplantation. 5 Methods to prevent sensitization would therefore have a broad therapeutic impact. 3 The power of MHC-specific antibodies to destroy vascularized allografts within minutes following transplantation has been appreciated since 1969. 6,7 Immunosuppressive drugs have been used to reduce the antibody response to allografts, 8,9 but the toxicity associated with the chronic use of these drugs is a significant limitation. Moreover, long-term outcomes are still significantly inferior. 10 Induction of mixed allogeneic chimerism has been demonstrated to confer donor-specific tolerance in the setting of allosensitization. 8,11 However, to establish mixed chimerism in sensitized recipients, the immune barrier from allosensitization must be overco...

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Section: Secondary Skin Graft Survival and Donor-specific Ab Generationmentioning

confidence: 99%

Costimulatory blockade of CD154-CD40 in combination with T-cell lymphodepletion results in prevention of allogeneic sensitization

Yan

Huang

et al. 2008

Blood

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“…We next performed immunophenotyping on whole blood samples shipped overnight from the collection site to a centralized flow cytometry facility. Subsets for analysis were selected from the 32 possible combinations of each 5-color panel (i.e., 2 5 ). Each unique combination based on the selected region combinations used (approximately 15 per panel) were treated as independent variables for the purposes of statistical analysis of the flow data in total.…”

Section: Study Population Clinical Characteristicsmentioning

confidence: 99%

“…However, similar improvements in long-term outcomes have not yet been achieved, and concerns over the morbidity of lifelong regimens of immunosuppressive drugs remain (1,2). Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is therefore a highly desirable therapeutic goal in kidney transplantation (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Identification of a B cell signature associated with renal transplant tolerance in humans

et al. 2010

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Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is a highly desirable therapeutic goal in solid organ transplantation. Determining which recipients would benefit from withdrawal or minimization of immunosuppression would be greatly facilitated by biomarkers predictive of tolerance. In this study, we identified the largest reported cohort to our knowledge of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs as well as healthy controls. In addition to being associated with clinical and phenotypic parameters, renal allograft tolerance was strongly associated with a B cell signature using several assays. Tolerant subjects showed increased expression of multiple B cell differentiation genes, and a set of just 3 of these genes distinguished tolerant from nontolerant recipients in a unique test set of samples. This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. These results point to a critical role for B cells in regulating alloimmunity and provide a candidate set of genes for wider-scale screening of renal transplant recipients.

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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%

“…Several review papers are available in the literature, providing in‐depth discussion of the putative mechanisms of operational and transplantation tolerance 5, 9–16. Such detailed description is beyond the scope of this work.…”

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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Transplantation tolerance in pediatric recipients: Lessons and challenges

Cited by 9 publications

References 123 publications

Costimulatory blockade of CD154-CD40 in combination with T-cell lymphodepletion results in prevention of allogeneic sensitization

Costimulatory blockade of CD154-CD40 in combination with T-cell lymphodepletion results in prevention of allogeneic sensitization

Identification of a B cell signature associated with renal transplant tolerance in humans

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

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