Mixed Xenogeneic Chimerism Induces Donor-Specific Humoral and Cellular Immune Tolerance for Cardiac Xenografts

Abstract

Xenotransplantation has been suggested as a potential solution to the critical shortage of donor organs. However, success has been limited by the vigorous rejection response elicited against solid organs transplanted across species barriers. Mixed xenogeneic bone marrow chimeras resulting from the transplantation of a mixture of host and donor marrow (B10 mouse + F344 rat → B10 mouse) results in donor-specific cross-species transplantation tolerance for subsequent nonvascularized skin and islet grafts. Furthermore, compared with fully xenogeneic chimeras (rat → mouse), mixed xenogeneic chimeras exhibit superior immunocompetence for infectious agents in vivo and in vitro, suggesting that the immune system is intact. The ability to establish long-term humoral and cellular tolerance for primarily vascularized xenografts in vivo, in the setting of both recipient and donor Ig and effector cell production, has not previously been characterized. Mixed xenogeneic chimeras exhibit donor-specific humoral tolerance as evident by the absence of anti-donor Ab and Ab-dependent donor-specific cytotoxicity in vitro and intravascular IgM deposition within donor-strain (F344) cardiac xenografts in vivo. F344 cardiac xenografts are accepted (median ≥180 days) without clinical or histologic evidence of rejection, suggesting cellular tolerance. In contrast, MHC-disparate third-party mouse (B10.BR) and rat (ACI or WF) grafts are rejected (median of 23 and 41 days, respectively) in association with extensive mononuclear cell infiltration and vascular deposits of mouse IgM. These results demonstrate that mixed xenogeneic chimerism establishes donor-specific humoral and cellular tolerance and permits the successful transplantation of even primarily vascularized xenografts in the setting of intact Ab production.

Evidence That FoxP3+ Regulatory T Cells May Play a Role in Promoting Long-Term Acceptance of Composite Tissue Allotransplants

“…In 1985, Ildstad et al (18), demonstrated that mixed chimerism induces tolerance to skin allografts and xenografts. Mixed chimerism has been shown to induce tolerance to cardiac, lung, and composite tissue allografts (19-21) and has allowed for the development of lower-intensity conditioning approaches that reduce the risk associated with conditioning. To our knowledge, we were the first to develop a nonfunctional heterotopic hindlimb flap model to show long-term tolerance to CTA using a nonmyeloablative conditioning approach (22).…”

Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure

“…Chimeric mice were generated adapting previously published methods (Supplemental Figure 1) [4]. CD45.1 C57BL/6 mice received 950-cGy lethal dose total body irradiation (TBI) from a 137 Cesium source (Nordion) for bone marrow (BM) ablation, followed by reconstitution with syngeneic donor BM 4–6 h later under sterile conditions.…”

Humoral immunity is the dominant barrier for allogeneic bone marrow engraftment in sensitized recipients

“…Similarly, in xenotransplantation, mixed chimerism is associated with decreased natural anti-Gal antibody production 29 and induction of B-cell tolerance to xenografts. 30 An understanding of the mechanism of sensitization and control of humoral immunity will allow the development of approaches to induce immune deviation in sensitized recipients. Of note, we found a difference between the response of allosensitization to BMCs and the response to solid organ grafts.…”

“…Mixed chimerism has been suggested as an approach to induce donor-specific tolerance in sensitized recipients 2,3 and may even allow the prolonged acceptance of xenografts. 4 A better understanding of the role that innate and adaptive immune responses play in allosensitization will allow a mechanistically driven approach to establish chimerism in sensitized recipients.…”