Anti‐<scp>CD</scp>2 producing pig xenografts effect localized depletion of human T cells in a hu<scp>SCID</scp> model

Brady, Jamie L.; Sutherland, Robyn M.; Hancock, Manuela S.; Kitsoulis, Susie; Lahoud, Mireille H.; Phillips, Peta; Hawthorne, Wayne J.; d’Apice, Anthony J.F.; Cowan, Peter J.; Harrison, Leonard C.; O’Connell, Philip J.; Lew, Andrew M.

doi:10.1111/xen.12025

Cited by 21 publications

(33 citation statements)

References 33 publications

(48 reference statements)

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“…High-dose (10 μg) OKT3 IP induced the production of multiple cytokines, namely; IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10 and IFN-γ, the concentrations of which increased over the 5-h time course ( Figure 4); TNF-α production was also induced but peaked earlier (at 1 h). As found previously, 10 cytokine concentrations returned to normal by 24 h. IL-12(p70) and IL-13 concentrations were very low (similar to the IgG-treated controls) and are not shown here. Hu-SCID mice that received the high-dose OKT3 IV were killed after 1 h (see above), and therefore cytokines could not be assayed Injection of 2 μg OKT3, whether IP or IV, induced very little detectable cytokine at any time point.…”

Section: Okt3supporting

confidence: 81%

Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu‐SCID model

et al. 2014

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Monoclonal antibodies (mAbs) have been a spectacular clinical and commercial success in the treatment of cancer and autoimmune diseases. Many of these mAbs (for example, OKT3, Campath-1H, rituximab and infliximab) are against surface or secreted products of lymphocytes. However, mAbs can have a variety of adverse effects including fever, chills and nausea. This is probably a result of cytokine release, which is most seriously manifested as a ‘cytokine storm' as highlighted by the TGN1412 (anti-CD28) trial. Prediction of adverse effects of mAbs would be clinically advantageous and numerous in vitro assays attempting to predict adverse effects have been reported. Here, we report an in vivo humanized mouse model to detect adverse effects in response to OKT3, Campath-1H or the polyclonal Ab preparation anti-thymocyte globulin. We found that the administration of each of these Abs to humanized mice led to acute clinical symptoms such as piloerection, hypomotility and hypothermia, particularly when delivered via the intravenous route. A cytokine storm occurred in the humanized mice receiving OKT3. This model system is a potentially useful tool to predict adverse effects and select initial doses for first-in-human trials. We would advocate this in vivo model, in addition to current in vitro preclinical testing, as a more representative and robust means of assessing potential adverse effects of mAb before their human use.

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Section: Okt3supporting

confidence: 81%

Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu‐SCID model

et al. 2014

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“…Whereas transgenic pCTLA4 expression in pigs seemed to compromise their immune system [48], beta cell-specific or ubiquitous LEA29Y expression had no deleterious effect on pig health or reproduction [49,50]. Pig-tomouse transplantation of anti-CD2-or LEA29-expressing islets benefited from CD3 + T-cell depletion and protection against human peripheral blood mononuclear cells respectively [47,49] but pig-to-primate transplantation of pCTLA4-expressing islets did not provide significant amelioration of long-term survival (less than 5 months) [51]. Indeed, comparable survival time was reported in non-human primates implanted with wild-type encapsulated islets without immunosuppression [29].…”

Section: Modification Of Donor Pigs To Mitigate the Immunementioning

confidence: 99%

“…A much more elegant approach would be to engineer islet cells to produce immunosuppressive antibodies or molecules locally at the graft site, thus preserving the islets and sparing the host from complications of systemic immunosuppression. Pig islets expressing anti-human CD2 [47], porcine cytotoxic T lymphocyte-associated antigen (pCTLA4) [48], or co-stimulatory signal inhibitor LEA29Y [49] have been described. Whereas transgenic pCTLA4 expression in pigs seemed to compromise their immune system [48], beta cell-specific or ubiquitous LEA29Y expression had no deleterious effect on pig health or reproduction [49,50].…”

Section: Modification Of Donor Pigs To Mitigate the Immunementioning

confidence: 99%

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Mourad

Gianello

2017

Curr Transpl Rep

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Purpose of Review Cell xenotransplantation has the potential to provide a safe, ethically acceptable, unlimited source for cell replacement therapies. This review focuses on genetic modification strategies aimed to overcome remaining hurdles standing in the way of clinical porcine islet transplantation and to develop neural cell xenotransplantation. Recent Findings In addition to previously described genetic modifications aimed to mitigate hyperacute rejection, instant blood-mediated inflammatory reaction, and cell-mediated rejection, new data showing the possibility of increasing porcine islet insulin secretion by transgenesis is an interesting addition to the array of genetically modified pigs available for xenotransplantation. Moreover, combining multiple modifications is possible today thanks to new, improved genomic editing tools. Summary Genetic modification of large animals, pigs in particular, has come a long way during the last decade. These modifications can help minimize immunological and physiological incompatibilities between porcine and human cells, thus allowing for better tolerance and function of xenocells.

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“…However, most trials using genetically engineered islets include systemic immunosuppression, which will limit the clinical applicability of this approach. In a recent study by Brady et al porcine islets have been generated that produce an anti-CD2 antibody, and cause local T-cell depletion at the site of engraftment in a humanized mouse model (53). Potentially, by combining a multitude of different genetic manipulations, effectively masking the porcine islets from detection by the recipient's immune system, while also producing local immunosuppressors, it might be feasible to reduce systemic immunosuppressive protocols, while maintaining graft survival and function (50,53).…”

Section: Xenotransplantationmentioning

confidence: 99%

Recent Advances in Cell Replacement Therapies for the Treatment of Type 1 Diabetes

Cogger

Nostro

2015

Endocrinology

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Exogenous insulin administration is currently the only treatment available to all type 1 diabetes patients, but it is not a cure. By helping to regulate circulating blood glucose levels, it has significantly improved life expectancy, but there are still long-term complications associated with the disease that may be preventable with a treatment strategy that can provide better glycemic control. Isolated islet (or whole pancreas) transplantation, xenotransplantation, and the transplant of human pluripotent stem cell-derived β-cells provide the potential to restore endogenous insulin production and reestablish normoglycemia. Here, we discuss the latest advances in these fields, including the use of encapsulation technology, as well as some of the hurdles that still need to be overcome for these alternative therapies to become mainstream and/or progress to clinical development.

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Anti‐CD2 producing pig xenografts effect localized depletion of human T cells in a huSCID model

Abstract: Local production of a single Ab against T cells can reduce graft infiltration at the xenograft site and may reduce the need for conventional, systemic immunosuppression.

Cited by 21 publications

References 33 publications

Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu‐SCID model

Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu‐SCID model

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Recent Advances in Cell Replacement Therapies for the Treatment of Type 1 Diabetes

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