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

Bracy, JL; Chase, Catharine M.; Russell, P. S.; Mauiyyedi, Shamila; Colvin, R. B.; Iacomini, John

doi:10.1038/sj.gt.3301581

Cited by 15 publications

(10 citation statements)

References 30 publications

(29 reference statements)

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“…34 As a solution to this problem, gene therapy has been applied in the BMT model using viral vectors to express ␣Gal. 17,35,36 The concept is to induce expression of ␣Gal on autologous BM cells and to use these cells for BMT to achieve chimerism and tolerance to the ␣Gal carbohydrate. This is thought to have a better practical prospect as it represents an alternative method of preventing hyperacute rejection due to xenoantibodies or anti-␣Gal Abs.…”

Section: Discussionmentioning

confidence: 99%

Tolerance induction by lentiviral gene therapy with a nonmyeloablative regimen

Mitsuhashi

Fischer-Lougheed

Shulkin

et al. 2006

Blood

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Antibodies (Abs) directed at the Gal␣1,3Gal␤1,4GlcNAc-R (␣Gal) carbohydrate epitope initiate xenograft rejection. Previously, we have shown that bone marrow transplantation (BMT) with lentivirus-mediated gene transfer of porcine ␣1,3 galactosyltransferase (GalT) is able to induce tolerance to ␣Gal-expressing heart grafts following a lethal dose of irradiation. Here we show the first demonstration of permanent survival of ␣Gal ؉ hearts following transplantation with autologous, lentivirus-transduced BM using a nonmyeloablative regimen. Autologous BM from GalT knockout (GalT ؊/؊ ) mice was transduced with a lentiviral vector expressing porcine GalT and transplanted into sublethally irradiated (3 Gy) GalT ؊/؊ mice. Chimerism in the peripheral blood cells (PBCs) remained low but was higher in the BM, especially within the stromal cell population. Mice reconstituted with GalT did not produce anti-␣Gal Abs over time. We immunized these mice with ␣Gal-expressing cells and assessed humoral immune responses. Anti-␣Gal xenoantibodies were not produced in mice reconstituted with GalT, but normal Ab responses to other xenoantigens were detected. Mice reconstituted with GalT accepted ␣Gal ؉ heart grafts over 100 days. IntroductionThe number of cases of organ transplantation has been increasing, however, the shortage of donor organs is a major problem because the number of donors is limited. Xenotransplantation using nonhuman species as organ donors has received much attention as a possible solution to this problem. Pigs are regarded as the most likely species to serve as donors for clinical xenotransplantation. 1 All mammals except humans, apes, and old-world monkeys express ␣1,3 galactosyltransferase (GalT), hence Gal␣1,3Gal␤1, 4GlcNac-R (␣Gal) is expressed on most tissues including vascular endothelium. [2][3][4] However, as humans have natural antibodies (Abs) against ␣Gal, it is known that xenotransplantation of pig organs into humans induces hyperacute rejection, acute vascular rejection/ delayed xenograft rejection, and even chronic rejection against ␣Gal. [5][6][7] In pig-to-primate discordant combination, 80% to 90% of antipig xenogeneic Abs are anti-␣Gal Abs. 8 Therefore, overcoming this response is presently the biggest problem facing xenotransplantation.To solve this problem, various approaches have been proposed. [9][10][11][12][13] Mixed hematopoietic chimerism can induce tolerance in allogeneic and xenogeneic models of transplantation. 14,15 Recently, it has been shown that tolerance to ␣Gal can be induced in GalT knockout (GalT Ϫ/Ϫ ) mice that produce anti-␣Gal Abs. Yang et al 16 applied mixed-cell chimerism to achieve permanent acceptance of transplanted organs by injecting bone marrow (BM) from wildtype (WT) donor mice into GalT Ϫ/Ϫ mice conditioned with irradiation and T-cell depletion. Bracy et al 17 have reported use of gene therapy to induce chimerism and tolerance following transplantation of autologous BM cells expressing a retrovirally transduced gene encoding GalT. We have reported that donor hearts...

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Section: Discussionmentioning

confidence: 99%

Tolerance induction by lentiviral gene therapy with a nonmyeloablative regimen

Mitsuhashi

Fischer-Lougheed

Shulkin

et al. 2006

Blood

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“…By introduction of aGT into syngeneic BMC B cell tolerance through molecular chimerism can be studied. Long-term molecular chimerism and B cell tolerance were achieved even when mice were pre-sensitized with pig cells and cardiac grafts from aGT expressing mice were accepted in GT 0 mice Iacomini 2000, 2002;Bracy et al 1998Bracy et al , 2001Kearns-Jonker et al 2004;Mitsuhashi et al 2006). Autologous transduced BMC expressing aGT was also transplanted into rhesus monkeys and xenoantibody production was strongly reduced after sensitization with porcine cells ).…”

Section: Introduction Of Allo-and Xeno-genes To Establish Tolerancementioning

confidence: 99%

Cell-Based Therapy in Allergy

Baranyi

Gattringer

Valenta

et al. 2011

Vaccines Against Allergies

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IgE-mediated allergy is an immunological disorder occurring in response to otherwise harmless environmental antigens (i.e., allergens). Development of effective therapeutic or preventive approaches inducing robust tolerance toward allergens remains an unmet goal. Several experimental tolerance approaches have been described. The therapeutic use of regulatory T cells (Tregs) and the establishment of molecular chimerism are two cell-based strategies that are of particular interest. Treg therapy is close to clinical application, but its efficacy remains to be fully defined. Recent proof-of-concept studies demonstrated that transplantation of syngeneic hematopoietic stem cells modified in vitro to express a major allergen leads to molecular chimerism and robust allergen-specific tolerance. Here we review cell-based tolerance strategies in allergy, discussing their potentials and limitations.

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“…The application of gene therapy as a means to achieve tolerance was first reported in aGT À/À knockout mice transplanted with BM, transduced with a murine retrovirus encoding the aGT enzyme. 8 We reported that permanent tolerance to gal + hearts can be achieved in this animal model using lentiviral vectors, 9 and Ogawa et al 10 reported similar results using transfer of adenovirus-transduced, autologous splenic lymphocytes. More recently, we have shown that aGT-encoding lentivectors can achieve sufficient chimerism in aGT À/À mice to result in permanent tolerance to gal + hearts following sublethal irradiation.…”

Section: Introductionmentioning

confidence: 54%