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Donor CD47 controls T cell alloresponses and is required for tolerance induction following hepatocyte allotransplantation.

ABSTRACT: CD47-deficient hepatocyte transplantation induces rapid innate immune cell activation and subsequent associated graft loss in syngeneic recipients. However, the role of donor CD47 in regulation of T-cell alloresponses is poorly understood. We addressed this question by assessing OVA-specific immune responses in mice following hepatocyte transplantation from CD47-competent or -deficient OVA-transgenic donors. Compared to sham-operated controls, intrasplenic transplantation of CD47-deficient OVA(+) hepatocytes significantly accelerated rejection of OVA(+) skin grafted 7 days after hepatocyte transplantation. In contrast, mice receiving CD47-competent OVA(+) hepatocytes showed prolonged and even indefinite survival of OVA(+) skin allografts. T cells from mice receiving CD47-deficient, but not CD47-competent, OVA(+) hepatocytes showed significantly enhanced responses to OVA(+) stimulators compared to sham-operated controls. In contrast to the production of tolerogenic cytokines (IL-4 and IL-10) in the recipients of CD47-competent hepatocytes, mice receiving CD47-deficient hepatocytes showed elevated production of IFN-? and IL-1?. Moreover, significant expansion of myeloid-derived suppressor cells was detected in the recipients of CD47-competent hepatocytes, which was required for tolerance induction in these mice. Thus, donor CD47 plays an important role in the control of T-cell alloresponses and tolerance induction following hepatocyte transplantation. Our data also suggest that intrasplenic hepatocyte transplantation may provide a means to induce allograft tolerance.

SUBMITTER: Zhang M

PROVIDER: S-EPMC4882503 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Donor CD47 controls T cell alloresponses and is required for tolerance induction following hepatocyte allotransplantation.

Zhang Mingyou M Wang Hui H Tan Shulian S Navarro-Alvarez Nalu N Zheng Yang Y Yang Yong-Guang YG

Scientific reports 20160527

CD47-deficient hepatocyte transplantation induces rapid innate immune cell activation and subsequent associated graft loss in syngeneic recipients. However, the role of donor CD47 in regulation of T-cell alloresponses is poorly understood. We addressed this question by assessing OVA-specific immune responses in mice following hepatocyte transplantation from CD47-competent or -deficient OVA-transgenic donors. Compared to sham-operated controls, intrasplenic transplantation of CD47-deficient OVA(+ ...[more]

PMID: 27230788

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Project description:BackgroundVascularized composite allotransplantation of the eye is an appealing, novel method for reconstruction of the nonfunctioning eye. The authors' group has established the first orthotopic model for eye transplantation in the rat. With advancements in immunomodulation strategies together with new therapies in neuroregeneration, parallel development of human surgical protocols is vital for ensuring momentum toward eye transplantation in actual patients.MethodsCadaveric donor tissue harvest (n = 8) was performed with orbital exenteration, combined open craniotomy, and endonasal approach to ligate the ophthalmic artery with a cuff of paraclival internal carotid artery, for transection of the optic nerve at the optic chiasm and transection of cranial nerves III to VI and the superior ophthalmic vein at the cavernous sinus. Candidate recipient vessels (superficial temporal/internal maxillary/facial artery and superficial temporal/facial vein) were exposed. Vein grafts were required for all anastomoses. Donor tissue was secured in recipient orbits followed by sequential venous and arterial anastomoses and nerve coaptation. Pedicle lengths and calibers were measured. All steps were timed, photographed, video recorded, and critically analyzed after each operative session.ResultsThe technical feasibility of cadaveric donor procurement and transplantation to cadaveric recipient was established. Mean measurements included optic nerve length (39 mm) and caliber (5 mm), donor artery length (33 mm) and caliber (3 mm), and superior ophthalmic vein length (15 mm) and caliber (0.5 mm). Recipient superficial temporal, internal maxillary artery, and facial artery calibers were 0.8, 2, and 2 mm, respectively; and superior temporal and facial vein calibers were 0.8 and 2.5 mm, respectively.ConclusionThis surgical protocol serves as a benchmark for optimization of technique, large-animal model development, and ultimately potentiating the possibility of vision restoration transplantation surgery.Clinical question/level of evidenceTherapeutic, V.

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Donor CD47 controls T cell alloresponses and is required for tolerance induction following hepatocyte allotransplantation.

Publications

Donor CD47 controls T cell alloresponses and is required for tolerance induction following hepatocyte allotransplantation.

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