Mixed Allogeneic Chimerism And Renal Allograft Tolerance In Cynomolgus Monkeys

Kawai, Tatsuo; Cosimi, A. Benedict; Colvin, Robert B.; Powelson, John A.; Eason, James D.; Kozlowski, Tomacsz; Sykes, Megan; Monroy, Rod; Tanaka, Mayumi; Sachs, David H.

doi:10.1097/00007890-199501270-00018

Cited by 169 publications

(238 citation statements)

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“…11 Indeed, it has been known for many years that a state of mixed (donor and host) hematopoietic chimerism, induced by bone marrow transplantation, can lead to permanent tolerance of T and B cells across allogeneic and concordant xenogeneic species barriers. [12][13][14][15][16][17] However, because bone marrow transplantation across discordant xenogeneic barriers has not yet been successful for a variety of reasons, this approach is not clinically applicable as a means of inducing tolerance to αGal. Building on the concept of using mixed chimerism to induce tolerance, we have developed an alternative approach using retroviral gene therapy to introduce a functional αGT gene into autologous bone marrow-derived cells to establish molecular rather than cellular chimerism.…”

Section: Introductionmentioning

confidence: 99%

Induction of molecular chimerism by gene therapy prevents antibody-mediated heart transplant rejection

et al. 2001

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Section: Introductionmentioning

confidence: 99%

Induction of molecular chimerism by gene therapy prevents antibody-mediated heart transplant rejection

et al. 2001

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“…The ability of mixed hematopoietic chimerism, in which T-cell depletion is used to kill mature alloreactive T cells and facilitate bone marrow engraftment 22 ; to induce tolerance in humans 23,24 or primates 25 clearly shows that this is not the case, and emphasizes some of the unique features of that approach. In the specific case of tolerance to vascularized allografts induced by DST and costimulatory blockade, a key issue may be whether or not T-cell depletion is complete.…”

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confidence: 99%

Homeostatic proliferation is a barrier to transplantation tolerance

Bensinger

Zhang

et al. 2003

Nat Med

386

362

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Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells 1,2 . Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials [3][4][5][6] . But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation 7,8 , may induce acquisition of functional memory T cells 9-13 . Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.T cells undergo homeostatic proliferation when transferred into severe combined immunodeficiency (scid), recombination-activating gene-deficient or irradiated recipients7 ,8 . In many clinical transplantation protocols, T-cell depletion is less profound. We therefore asked whether residual nondepleted cells could undergo homeostatic proliferation. We treated mice with two doses (100 μg/dose) of depleting monoclonal antibodies directed at CD4 and CD8 (days 0 and 5). This induced 80-90% T-cell depletion, which was maintained for >10 d after the last dose (data not shown).

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“…Transplant tolerance is expected to be a way, to both reduce rejection and minimize immunosuppressive side effects, therefore improving graft outcome. A better understanding of basic tolerogenic mechanisms (clonal exhaustion, deletion, and immune ignorance) as well as the capital role that T cells play during transplant rejection has resulted in different strategies trying to induce tolerance (1)(2)(3)(4)(5)(6); namely, T cell costimulation blockade, mixed chimerism induction, T cell depletion, and tolerance mediated by regulatory T cells (Tregs). 3 It is to note that some of these approaches have been already successfully proven in murine and in nonhuman primate models (7)(8)(9)(10)(11)(12).…”

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confidence: 99%

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

Bestard¹,

Cruzado²,

Mestre³

et al. 2007

The Journal of Immunology

146

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Exploring new immunosuppressive strategies inducing donor-specific hyporesponsiveness is an important challenge in transplantation. For this purpose, a careful immune monitoring and graft histology assessment is mandatory. Here, we report the results of a pilot study conducted in twenty renal transplant recipients, analyzing the immunomodulatory effects of a protocol based on induction therapy with rabbit anti-thymocyte globulin low doses, sirolimus, and mofetil mycophenolate. Evolution of donor-specific cellular and humoral alloimmune response, peripheral blood lymphocyte subsets and apoptosis was evaluated. Six-month protocol biopsies were performed to assess histological lesions and presence of FOXP3+ regulatory T cells (Tregs) in interstitial infiltrates. After transplantation, there was an early and transient apoptotic effect, mainly within the CD8+HLADR+ T cells, combined with a sustained enhancement of CD4+CD25+high lymphocytes in peripheral blood. The incidence of acute rejection was 35%, all steroid sensitive. Importantly, only pretransplant donor-specific cellular alloreactivity could discriminate patients at risk to develop acute rejection. Two thirds of the patients became donor-specific hyporesponders at 6 and 24 mo, and the achievement of this immunologic state was not abrogated by prior acute rejection episodes. Remarkably, donor-specific hyporesponders had the better renal function and less chronic renal damage. Donor-specific hyporesponsiveness was inhibited by depleting CD4+CD25+high T cells, which showed donor-Ag specificity. FOXP3+CD4+CD25+high Tregs both in peripheral blood and in renal infiltrates were higher in donor-specific hyporesponders than in nonhyporesponders, suggesting that the recruitment of Tregs in the allograft plays an important role for renal acceptance. In conclusion, reaching donor-specific hyporesponsiveness is feasible after renal transplantation and associated with Treg recruitment in the graft.

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Mixed Allogeneic Chimerism And Renal Allograft Tolerance In Cynomolgus Monkeys

Cited by 169 publications

References 0 publications

Induction of molecular chimerism by gene therapy prevents antibody-mediated heart transplant rejection

Induction of molecular chimerism by gene therapy prevents antibody-mediated heart transplant rejection

Homeostatic proliferation is a barrier to transplantation tolerance

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

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