Effects of Lung Cotransplantation on Cardiac Allograft Tolerance Across a Full Major Histocompatibility Complex Barrier in Miniature Swine

Abstract

A 12-day course of high-dose tacrolimus induces tolerance of major histocompatibility complexmismatched lung allografts in miniature swine but does not induce tolerance of heart allografts unless a kidney is cotransplanted. To determine whether lungs share with kidneys the ability to induce cardiac allograft tolerance, we investigated heart-lung cotransplantation using the same induction protocol. Hearts (n ¼ 3), heart-kidneys (n ¼ 3), lungs (n ¼ 6), and hearts-lungs (n ¼ 3) were transplanted into fully major histocompatibility complex-mismatched recipients treated with high-dose tacrolimus for 12 days. Serial biopsy samples were used to evaluate rejection, and in vitro assays were used to detect donor responsiveness. All heart-kidney recipients and five of six lung recipients demonstrated long-term graft survival for longer than 272 days, while all heart recipients rejected their allografts within 35 days. Tolerant recipients remained free of alloantibody and showed persistent donor-specific unresponsiveness by cellmediated lympholysis/mixed-lymphocyte reaction. In contrast, heart-lung recipients demonstrated rejection of both allografts (days 47, 55, and 202) and antidonor responsiveness in vitro. In contrast to kidneys, lung cotransplantation leads to rejection of both heart and lung allografts, indicating that lungs do not have the same tolerogenic capacity as kidneys. We conclude that cells or cell products present in kidney, but not heart or lung allografts, have a unique capacity to confer unresponsiveness on cotransplanted organs, most likely by amplifying host regulatory mechanisms.

Apoptotic cell-based therapies for promoting transplantation tolerance

“…[29 ■ ] show that a tolerance protocol constituted of nonmyeloablative irradiation with donor-specific transfusion (DST) and immuno-suppression, while providing prolonged protection to the lung allografts, fails to promote heart allograft survival. Such organ-specific heterogeneity has also been observed in other nonapoptotic cell-based tolerance regimens [28]. For example, Madariaga et al .…”

“…Such a difference in tolerance efficacy by donor ECDI-SP may be attributed to the difference in allogeneic endothelial targets present in the allogeneic heart, but not in islets. Interestingly, even among solid organs (lung versus heart), efficacy of tolerance varies dramatically [28,29 ■ ]. In full-mismatched miniature swine cardiac and lung transplant models, Sommer et al .…”

“…For example, Madariaga et al . [28] demonstrate that tacrolimus induces tolerance to lung allografts, whereas cardiac allografts are readily rejected unless they are co-transplanted with the same donor kidney, suggesting the tolerogeneicity of kidneys possibly owing to Treg induction by kidney tubular epithelial cells. These data thus underscore the need for a better understanding of organ-specific factors underlying tolerance susceptibility for the design of apoptotic cell-based organ-specific tolerance protocols.…”

Induction of Tolerance towards Solid Organ Allografts Using Hematopoietic Cell Transplantation in Large Animal Models

“…Swine, and miniature swine in particular, have been useful large animal models with which to study HCT-induced tolerance induction for solid organ transplantation [55][56][57][58]. As in all HCT models, the characterization of the major histocompatibility complex in miniature swine, known as the miniature swine leukocyte antigen (MSLA) complex, is required in order to assess the level of identity and transplantation success.…”

Irradiation before and donor splenocyte infusion immediately after transplantation induce tolerance to lung, but not heart allografts in miniature swine

“…described long‐term tolerance in miniature swine receiving a single‐lung transplantation and a 12‐day course of high‐dose tacrolimus, but transferring the same protocol to heart allografts failed. Interestingly, long‐term tolerance towards heart allografts was induced when a kidney co‐transplantation was performed with the heart, with kidneys known to be tolerance‐prone organs in those investigators’ previous work .…”