Mixed Hematopoietic Chimeras Research Articles

Tolerance to vascularized kidney grafts in canine mixed hematopoietic chimeras.

Recent progress in allogeneic hematopoietic stem cell transplantation provides new methods for reliable engraftment with nonlethal conditioning regimens. These techniques have been successfully applied in the treatment of both malignant and nonmalignant diseases, but have not been fully exploited for their potential to tolerize recipients for organ transplantation. These studies were undertaken to test whether the tolerance of host immune cells toward donor hematopoietic cells in mixed hematopoietic chimeras extends to include a vascularized organ, the kidney. Using nonmyeloablative doses of total body irradiation, a short course of immunosuppression, and hematopoietic stem cells from marrow or peripheral blood sources, five dog lymphocyte antigen-identical canines were made to become stable mixed hematopoietic chimeras with no development of graft-versus-host disease or posttransplant lymphoproliferative disorder. Subsequently, renal transplantations were performed between stem cell donor and recipient littermates, and no additional immunosuppressive therapy was given after stem cell transplantation. All mixed chimeric dogs demonstrate different, but stable, levels of donor peripheral blood lymphocyte and granulocyte chimerism. With follow-up of longer than 1 year, all of the mixed chimeric dogs (five/five) have excellent renal function with normal serum creatinines (<1.5 mg/dl) and no pathological evidence of rejection on biopsies. In a major histocompatibility-matched model, minor antigen differences between donor and recipient are not sufficient to induce a host immune response to a vascularized kidney transplant in mixed hematopoietic chimeras.

A role for donor-derived B cells but not T cells in the maintenance of mixed hematopoietic chimerism

ENGRAFTMENT of allogeneic pluripotent hematopoietic stem cells (PHSC) in nonmyeloablated but immunodepleted recipients can produce mixed hematopoietic chimeras in which both host and donor cells coexist and are tolerant of each other. The major mechanism of tolerance in these mixed chimeras is central intrathymic clonal deletion, which is induced and maintained by the immigration of both host and donor marrow-derived cells to the host thymus, ensuring the ongoing central deletion of donorand host-reactive thymocytes. In this study, we addressed the role of different donor-derived hematopoietic cells in the induction and maintenance of mixed hematopoietic chimerism and tolerance in mice receiving non-myeloablative conditioning.

Nonmyeloablative conditioning to induce bilateral tolerance after allogeneic bone marrow transplantation in mice

We recently described a new nonmyeloablative method to induce stable and specific transplantation tolerance to allogeneic tissues in adult mice. It included total lymphoid irradiation (TLI) of recipients with six fractions of 200 cGy each, inoculation with donor bone marrow (BM) cells and cyclophosphamide (Cy) for selective elimination or inactivation of residual donor-reactive cells of the host, and infusion with T-cell depleted donor BM cells after Cy. Here, we investigated the possibility to induce stable bilateral graft-vs-host and host-vs-graft transplantation tolerance using non–T-cell depleted allogeneic BM. Our results show that the dose of BM required for the induction of transplantation tolerance was inversely correlated with the intensity of the conditioning. Transfer of a low dose (3 × 10 6) of total donor BM cells to recipients preconditioned with a less intensive regimen (two or three TLI fractions instead of six) diminished graft-vs-host disease (GVHD)-related mortality of recipients to 40% and converted 89% of the survivors into GVHD-free mixed hematopoietic chimeras that maintained donor skin allografts >180 days. A tenfold increase in the number of donor BM cells (3 × 10 7 instead of 3 × 10 6) reduced the rate of GVHD-related mortality of recipients to 20% and resulted in bilateral transplantation tolerance in 100% of nonirradiated survivors.

Mixed hematopoietic chimerism and transplantation tolerance.

Durable transplantation tolerance can be reliably achieved by inducing engraftment of hematopoietic cells in recipients initially depleted of T-lymphocytes. Engraftment of donor pluripotent hematopoietic stem cells (PPHSC) produces mixed hematopoietic chimeras in which both host and donor cells coexist and are tolerant of each other. The major mechanism of tolerance in these chimeras is central, intrathymic clonal deletion, which is induced and maintained by immigration of both host and donor marrow-derived cells to the host thymus, ensuring the ongoing central deletion of donor- and host-reactive cells. In this article, approaches developed in our laboratory to induce stable mixed hematopoietic chimerism and specific central deletional allogeneic and xenogeneic tolerance without toxic or myeloablative host conditioning are reviewed.

Clonal deletion is one mechanism responsible for tolerance in mixed hematopoietic chimeras

Clonal deletion is one mechanism responsible for tolerance in mixed hematopoietic chimeras

Origin of hematopoietic progenitor cells after bone marrow transplantation: Analysis by means of a Y-chromosome specific DNA probe

To characterize hematopoietic cells in mixed hematopoietic chimeras after allogeneic bone marrow transplantation (BMT), the authors examined the origin of progenies derived from hematopoietic progenitor cells of male recipients who received a marrow graft from female donors, by use of a Y-chromosome specific DNA (YDNA) probe in combination with an in vitro colony assay. Host-type hematopoietic cells were detected in cultured bone marrow mononuclear cells (BMMC) from 4 out of 6 patients studied, who were all in complete remission. In 2 patients of the mixed chimeras, the relative amount of host-derived YDNA from BMMC increased after methylcellulose cultures for 14 days. Analysis of individual colonies derived from granulocyte-macrophage colony forming units (CFU-GM) from these mixed chimeras, including 2 patients with chronic myelogenous leukemia (CML), revealed approximately 30% of total colonies were host-type, although no evidence for the existence of residual Ph1 positive cells was obtained by using polymerase chain reaction for detecting bcr-abl chimeric messenger RNA in the 2 CML patients. These findings provide direct evidence that considerable numbers of host-derived normal hematopoietic progenitors survive and persist for a long term in a certain population of marrow recipients, after BMT following supralethal radiochemotherapy.