A strategy for organ allografts without using immunosuppressants or irradiation

Abstract

A strategy to achieve regular and long lasting organ and tissue allografts without using immunosuppressants and͞or irradiation has been established for mice. One hundred percent of skin allografts can be induced to survive >350 days after transplantation if spleen cells from the same donors are first injected into the portal vein of the recipients. The mechanisms underlying this long-term tolerance induction can be described as follows: (i) donor T cells from the spleen of the donor facilitate the acceptance of the allogeneic engraftment, (ii) donor-specific anergy is induced in the cytotoxic T-lymphocytes of the recipients, (iii) T helper type 2 cells become the dominant T cells in the recipients that are accepting the skin transplants, and (iv) a lasting chimerism (microchimerism) is established in these recipients. This strategy, perhaps with minor modifications, might permit one also to overcome major barriers to organ allografting in humans. If this were the case, it could represent production of long lasting immunologic tolerance without need for irradiation or cytotoxic chemo-preparative regimen and as such could greatly facilitate allotransplantation free of episodes of chronic or acute rejection or toxic and damaging preparatory regimens.

Synergistic effects of injection of bone marrow cells into both portal vein and bone marrow on tolerance induction in transplantation of allogeneic pancreatic islets

“…20 In this experiment, we have also shown that the existence of donor hematopoietic cells is crucial for the survival of donor PIs. In addition, we have recently shown the same findings in the transplantation of combinations of BMCs and other organs or tissue (such as the skin, leg and lung 18,[37][38][39] as in PI transplantation. Pham et al 40 and Foster et al 41 have also shown the importance of the existence of donor hematopoietic cells for the acceptance of the lung and composite tissue in the transplantation of the combination of BMCs and organs.…”

“…[14][15][16] We have developed more effective bone marrow transplantation (BMT) methods for the induction of acceptance of donor bone marrow cells (BMCs) than conventional intravenous injection of BMCs (IV-BMT); one method is BMC-transplantation into the liver via the PV (PV-BMT) and the other is intra-bone marrow (IBM)-BMT. [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Based on our findings, we have developed a strategy to permit the long-term acceptance of allogeneic PIs by intra-hepatic transplantation of PIs plus whole-donor BMCs, followed by IV injection of whole BMCs on day 5 after PItransplantation without immunosuppressants in rats. 20 Although irradiation doses as pre-conditioning can be reduced in comparison with IV-administration of BMCs (IV-BMT), additional IV injection of BMCs is necessary in this method.…”

Administration of an Antigen at a High Dose Generates Regulatory CD4+ T Cells Expressing CD95 Ligand and Secreting IL-4 in the Liver

“…These anatomical features suggest that the liver may serve as a lymphoid organ wherein lymphocytes are activated by Ags circulating in the portal and arterial blood flow. In fact, administration of donor cells via the portal vein primes the recipient by the donor-Ags and leads to donor-Ag specific hyporesponsiveness (5)(6)(7)(8). Furthermore, the liver itself is such a tolerogenic organ that transplantation of an allogeneic liver sometimes requires little or no immunosuppressive therapy.…”

A New Method for Tolerance Induction: Busulfan Administration Followed by Intravenous Injection of Neuraminidase‐Treated Donor Bone Marrow

“…Recently, we have found that the engraftment of allogeneic BMCs was significantly enhanced by administering BMCs via the portal vein [12]. Furthermore, we have succeeded in inducing persistent donor-specific tolerance across major histocompatibility complex (MHC) barriers utilizing the intrahepatic tolerance-inducing system in mice [13] and pigs [14]; the injection of donor BMCs via the p.v. (on day 0) plus i.v.…”

“…The skin grafting was carried out as previously described [13] on the day (but not on day 7) after the injection of donor BMCs (Fig. 1).…”