Shimon Slavin

Mesenchymal stromal cells lose their immunosuppressive potential after allotransplantation

OBJECTIVEnThe stem cell fraction of mesenchymal stromal cells (MSCs) is capable of self-renewal and under inductive conditions differentiates into bone, cartilage, hematopoietic stroma, and other mesenchymal tissues. Therefore, MSCs represent a promising source for hard tissue repair therapies. MSCs are also immunosuppressive and prevent activation of allogeneic lymphocytes in vitro. Thus it has been suggested that they might be able to engraft in allogeneic recipients and downregulate recipients immunity. In this study we examined whether MSCs retain their immunomodulating properties in vivo after allotransplantation.nnnMATERIALS AND METHODSnMSCs were propagated from bone marrow (BM), placenta, or umbilical cord tissues. Using a murine parental-into-F1 model of graft-vs-host disease (GVHD) we tried to control GVHD by intravenous transplanting parental or recipient MSCs together with parental lymphocytes (day 0) and on days +7 and +14. MSCs immunosuppressive potential in vivo was also examined by comparing their ability to construct ectopic bone after local transplantation with osteogenic inductor (demineralized bone matrix) under the kidney capsule of syngeneic and allogeneic recipients.nnnRESULTSnRepeated IV MSC injections failed to reduce GVHD-related recipient mortality. Local implantation of MSCs propagated from BM, placenta or umbilical cord resulted in ectopic bone formation in syngeneic recipients and in transplant rejection by allogeneic mice.nnnCONCLUSIONnMSCs lose their immunosuppressive potential in mismatched setting.

A COMPARISON OF HLA-IDENTICAL SIBLING ALLOGENEIC VERSUS AUTOLOGOUS TRANSPLANTATION FOR DIFFUSE LARGE B-CELL LYMPHOMA: A REPORT FROM THE CIBMTR

We compared outcomes of 916 diffuse large B cell lymphoma (DLBCL) patients aged >or=18 years undergoing first autologous (n = 837) or myeloablative (MA) allogeneic hematopoietic cell transplant (HCT) (n = 79) between 1995 and 2003 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Median follow-up was 81 months for allogeneic HCT versus 60 months for autologous HCT. Allogeneic HCT recipients were more likely to have high-risk disease features including higher stage, more prior chemotherapy regimens, and resistant disease. Allogeneic HCT was associated with a higher 1 year treatment-related mortality (TRM) (relative risk [RR] 4.88, 95% confidence interval [CI], 3.21-7.40, P < .001), treatment failure (RR 2.06, 95% CI, 1.54-2.75, P < .001), and mortality (RR 2.75, 95% CI, 2.03-3.72, P < .001). Risk of disease progression was similar in the 2 groups (RR 1.12, 95% CI, 0.73-1.72, P = .59). In fact, for 1-year survivors, no significant differences were observed for TRM, progression, progression-free (PFS) or overall survival (OS). Increased risks of TRM and mortality were associated with older age (>50 years), lower performance score, chemoresistance, and earlier year of transplant. In a cohort of mainly high-risk DLBCL patients, upfront MA allogeneic HCT, although associated with increased early mortality, was associated with a similar risk of disease progression compared to lower risk patients receiving autologous HCT.

Prevention of acute graft-vs-host disease by a single low-dose cyclophosphamide injection following allogeneic bone marrow transplantation

OBJECTIVEnPreviously, we documented that conditioning based on donor-specific cell transfusion (DST) and subsequent selective depletion of activated donor-reactive cells by cyclophosphamide (CY) facilitates alloengraftment in a murine transplantation model. Transplantation event represents a strong immunogenic stimulus for host-reactive donor T cells that induce graft-vs-host disease (GVHD). Therefore, in this study, we addressed the question of whether a single posttransplantation CY administration (CY2) can prevent acute GVHD-related mortality without compromising engraftment of allogeneic transplant.nnnMATERIALS AND METHODSnSplenocyte-enriched C57BL/6 bone marrow was transplanted to BALB/c recipients after mild irradiation, and conditioning with DST and 100 mg/kg CY. Following transplantation, recipients were left untreated or given on a specified day a single CY2 injection (50 mg/kg). All animals were monitored for survival, chimerism, and clinical signs of GVHD. Experimental mice that received BCL1 leukemia cells before transplantation were monitored for leukemia-related mortality as well.nnnRESULTSnAnimals that received no CY2 after transplantation died of acute GVHD. A single low-dose CY2 treatment within the first 5 days after transplantation prevented mortality in most recipients. However, only CY2 administration on days +1 or +5 preserved chimerism. Most chimeras survived GVHD-free for >200 days. Prolonged persistence of host-reactive T cells in mice (CY2 on day +5) permitted a reduction to be made in engraftment-essential irradiation dose and preserved a strong graft-vs-leukemia effect of transplantation.nnnCONCLUSIONnAcute GVHD can be prevented in mice by a single properly timed posttransplantation low-dose CY administration.

Bone Marrow Transplantation for Cancer and Autoimmunity

Publisher Summary High dose chemoradiotherapy supported by autologous blood or marrow stem cell transplantation (autoBMT) and allogeneic blood or marrow stem cell transplantation (alloBMT) result in effective control of autoimmune diseases. There appears to be a two-way relationship between autoimmunity and both autoBMT and alloBMT. Following transplantation, patients may develop complications due to abnormal regulation of the newly developing immune system, thus resulting in autoimmune manifestations of disease. On the other hand, both autoBMT and alloBMT are used not only for the treatment of an autoimmune disease that accompanies primary malignancy, but also as the primary treatment of life-threatening autoimmune diseases with encouraging results. This chapter reviews various clinical syndromes to examine the association between auto and alloBMT and autoimmunity. The use of alloBMT and autoBMT for the treatment of otherwise resistant hematologic malignancies and certain chemotherapy sensitive solid tumors, respectively, is well established. The chapter describes the rationale for the use of autoBMT and alloBMT for the treatment of autoimmune disorders. A standard autoBMT as well as alloBMT appear most suitable in patients with hematologic malignancies and solid tumors sensitive to chemoradiotherapy, because the rescue procedure enables administration of higher than conventional doses of cytoreductive antitumor agents. Following myeloablative chemoradiotherapy supported by autoBMT, the rate of anticipated relapse is much higher because of the lack of graft versus leukemia (GVL) effects mediated by alloreactive donor-derived T cells. Many approaches have been developed to to improve antitumor effects induced by donor T cells.

ANTILEUKEMIC EFFECTS OF ALLOGENEIC BONE MARROW ALLOGRAFTS IN MICE

ABSTRACT The murine B cell leukemia (BCL 1 ) of BALB/c mice was used as a tumor model to study the role of allogeneic bone marrow transplantation as a curative anti-tumor modality. BCL 1 disease was eliminated and tumor-specific-IgM λ-idiotype-positive cells were undetectable in tumor bearing (BALB/c × C57B1/6)F 1 mice (F 1 ) conditioned with total lymphoid irradiation and cytoreduced with cyclophosphamide following transplantation with incompatible (A/J and C57B1/6) but not compatible (BALB/c and F 1 ) marrow allografts. No tumor was identifiable in 50% of mice by adoptive transfer of 10 6 spleen cells into naive BALB/c recipients. Coinjection of 10 6 spleen cells obtained from “cured” A/J→F 1 and C57Bl/6→F 1 chimeras with 10 2 -10 5 BCL 1 cells into naive BALB/c recipients resulted in delayed onset of leukemia in two separate experiments. Transfer of 20 × 10 6 spleen cells from cured A/J→F 1 chimeras with 10 6 BCL 1 cells failed to inhibit onset of leukemia. The data suggest that graft-versus-leukemia may be operating by active cell mediated mechanisms of allogeneic but not syngeneic origin.

Mixed chimerism following non-myeloablative stem cell transplantation (Nst) To induce transplantation tolerance to bone marrow and organ allografts

Abstract Durable engraftment of donor hematopoietic stem cells results in long lasting transplantation tolerance to donor alloantigens; mixed chimerism (MC) induced during fetal life or neonatally, results in life-long transplantation tolerance to donor alloantigens, using no pre- or post transplant immunosuppression. We showed previously that induction of MC in immunocompetent recipients conditioned by total lymphoid irradiation (TLI) results in permanent, specific transplantation tolerance to donor alloantigens with permanent engraftment of heart, pancreatic islets and full thickness skins. MC can be clinically induced by non-myeloablative stem cell transplantation. Host hematopoietic cells in MC may down-regulate donor anti-host alloreactivity, minimizing graft vs host disease, immunocompetent donor T lymphocytes may facilitate engraftment of donor hematopoietic cells, down-regulating residual host immunocompetent lymphocytes. Data from C57BL/6→ BALB/c chimeras show that MC with bilateral transplantation tolerance is inducible by deletion of host anti-donor alloreactive cells through activation-induced apoptosis, after stimulation of activated lymphocytes by donor alloantigens. Here we have induced host vs graft and graft vs host transplantation tolerance using NST, i.e. 1–6 fractions of TLI 200 cGy each, followed by deletion of BALB/c and C57BL/6 anti-alloreactive T lymphocytes by cytoxan 120–200 mg/kg as preparation for a 2 nd bone marrow transplantation 1 day later. Recipients accept donor skin allografts permanently (>200 days). Induction of permanent transplantation tolerance to donor alloantigens to gradually replace host with donor hematopoietic cells in hematologic, genetic and autoimmune diseases will be presented.