Immunotoxin-treated rhesus monkeys: a model for renal allograft chronic rejection1

Torrealba, José; Fernández, Luis A.; Kanmaz, Turan; Oberley, Terry D.; Schultz, Jacqueline M.; Brunner, Kevin; Peters, David M.; Fechner, John H.; Dong, Yinchen; Hu, Huaizhong; Hamawy, Majed M.; Knechtle, Stuart J.

doi:10.1097/01.tp.0000075788.72614.d4

Cited by 38 publications

(36 citation statements)

References 26 publications

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“…Lymphocyte depletion prior to or beginning at the time of transplantation is beneficial in reducing maintenance immunosuppression (Calne et al 1998(Calne et al , 1999Swanson et al 2002;Kirk et al 2003;Starzl et al 2003;Torrealba et al 2003). Many depleting agents have been studied in animal models and clinical trials, and have been proven efficacious in reducing the rate of acute rejection when combined with maintenance regimens.…”

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confidence: 99%

Lymphodepletional Strategies in Transplantation

Page

Kwun

et al. 2013

Cold Spring Harbor Perspectives in Medicine

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Because lymphocytes were shown to mediate transplant rejection, their depletion has been studied as a mechanism of preventing rejection and perhaps inducing immunologic tolerance. Agents that profoundly deplete lymphocytes have included monoclonal antibodies, cytotoxic drugs, and radiation. We have studied several such agents but focused on antibodies that deplete not only peripheral blood lymphocytes, but also lymph node lymphocytes. Depletion of lymph node T lymphocytes appears to permit peripheral tolerance at least for T cells in animal models. Nevertheless, B-cell responses may be resistant to such approaches, and T memory cells are likewise relatively resistant to depleting antibodies. We review the experimental and clinical approaches to depletion strategies and outline some of the pitfalls of depletion, such as limitations of currently available agents, duration of tolerance, infection, and malignancy. It is notable that most tolerogenic strategies that have been attempted experimentally and clinically include depleting agents even when they are not named as the underlying strategy. Thus, there is an implicitly acknowledged role for reducing the precursor frequency of donor antigen-specific lymphocytes when approaching the daunting goal of transplant tolerance.

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confidence: 99%

Lymphodepletional Strategies in Transplantation

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Kwun

et al. 2013

Cold Spring Harbor Perspectives in Medicine

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“…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). In the clinical setting, tolerance or "prope" tolerance has been defined as evidence of donor-specific un/hyporesponsiveness with recovered third party response in functional in vitro assays, lack of circulating donor-specific alloantibodies and absence of destructive lymphocyte infiltration in allograft biopsies in patients without or with minimal amount of immunosuppression.…”

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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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“…Knechtle postulated that immunotoxin effectively ablated T cell mediated acute cellular rejection but did not prevent all T cell allosensitization thereby promoting later T-dependent alloantibody mediated graft loss (Armstrong et al 1998). This group has gone on to show that immunotoxin treated animals are a model for chronic graft rejection ( Torrealba et al 2003). These animals develop severe interstitial fibrosis, tubular atrophy, chronic transplant glomerulopathy and chronic vascular sclerosis.…”

Section: Depletional Approaches To Tolerance (A) Lymphoid Irradiationmentioning

confidence: 99%

Induction of transplantation tolerance in non-human primate preclinical models

Hale

Dhanireddy

Bruno

et al. 2005

Phil. Trans. R. Soc. B

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Short-term outcomes following organ transplantation have improved considerably since the availability of cyclosporine ushered in the modern era of immunosuppression. In spite of this, many of the current limitations to progress in the field are directly related to the existing practice of relatively non-specific immunosuppression. These include increased risks of opportunistic infection and cancer, and toxicity associated with long-term immunosuppressive drug exposure. In addition, long-term graft loss continues to result in part from a failure to adequately control the anti-donor immune response. The development of a safe and reliable means of inducing tolerance would ameliorate these issues and improve the lives of transplant recipients, yet given the improving clinical standard of care, the translation of new therapies has become appropriately more cautious and dependent on increasingly predictive preclinical models. While convenient and easy to use, rodent tolerance models have not to date been reliably capable of predicting a therapy's potential efficacy in humans. Non-human primates possess an immune system that more closely approximates that found in humans, and have served as a more rigorous preclinical testing ground for novel therapies. Prior to clinical adaptation therefore, tolerance regimens should be vetted in non-human primates to ensure that there is sufficient potential for efficacy to justify the risk of its application.

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Immunotoxin-treated rhesus monkeys: a model for renal allograft chronic rejection1

Cited by 38 publications

References 26 publications

Lymphodepletional Strategies in Transplantation

Lymphodepletional Strategies in Transplantation

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

Induction of transplantation tolerance in non-human primate preclinical models

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