Human-mouse lymphoid chimeras: host-vs.-graft and graft-vs.-host reactions (original) (raw)
Related papers
Experimental Hematology, 2004
Objective. To clarify natural killer (NK) cell-mediated resistance under cytoreductive conditioning and T cell-depleted bone marrow transplantation, we investigated the effects of host NK cell depletion on engraftment and induction of stable mixed chimerism. Methods. BALB/c mice (H-2k d) were injected intraperitoneally with anti-asialoGM1 antibody (anti-NK Ab) on day-1. On day 0, they received total body irradiation (TBI) at a dose of 500 cGy, followed by intravenous infusion of 2 × 10 7 T cell-depleted (TCD) bone marrow cells from C57BL/6 mice (H-2k b). Early engraftment and chimerism were determined by the relative ratio of peripheral blood (PB) lymphocytes expressing either H-2k d or H-2k b on day ϩ21. Long-term engraftment and chimerism were evaluated on PB and spleen by multicolor flow cytometry. Results. Although no recipients treated with TBI alone showed engraftment, all the recipients conditioned with anti-NK Ab and TBI showed successful engraftment as well as a donordominant pattern of mixed chimerism in both PB and spleen. Spleen cells from recipients with mixed chimerism showed specific tolerance to both host and donor strains, but not to a third party (C3H/He). None of the reconstituted mice showed signs of graft vs host disease, and all survived up to day ϩ330. Conclusion. These observations indicate that host NK cell depletion may be used to reduce the intensity of conditioning regimens for engraftment of TCD grafts, and can contribute to establishment of stable mixed chimerism in major histocompatibility complex-mismatched nonmyeloablative transplantation. Ć 2004 International Society for Experimental Hematology.
Transplantation, 2001
Background. Models of immunodeficient mice reconstituted with a competent human immune system would represent an invaluable tool for the study of transplantation immunobiology allergy, autoimmunity, and infectious diseases. Severe combined immune deficiency (scid) mice can be successfully reconstituted with human peripheral blood lymphocytes (PBLs), but rates and levels of engraftment are poor. New strains of mice with diverse immunodeficiencies have been recently characterized or developed, which might prove to be advantageous for in vivo studies of human immune reactivity.
Biology of Blood and Marrow Transplantation, 1999
Mixed hematopoietic chimerism can be induced in mice receiving allogeneic bone marrow transplantation (BMT) after nonmyeloablative host conditioning with depletion T cells with of anti-T cell monoclonal antibodies (mAbs), low-dose (3 Gy) total-body irradiation (TBI), and local thymic irradiation (7 Gy). These mice are specifically tolerant to donor and host antigens. When nontolerant donor T cells are given to chimeras several months after BMT, full donor-type chimerism develops, but graft-vs.-host disease (GVHD) does not occur. The induction of such lymphohematopoietic GVH reactions without GVHD could provide an approach to separating graft-vs.-leukemia (GVL) from GVHD in patients with hematologic malignancies. To make the nonmyeloablative conditioning regimen described above more cytoreductive for such malignancies, we have now modified it by replacing TBI with cyclophosphamide (CP). Treatment with anti-CD4 and anti-CD8 mAbs on day-5, 200 mg/kg CP on day-1, and 7 Gy thymic irradiation on day 0 was only slightly myelosuppressive and allowed fully major histocompatibility complex (MHC)-mismatched (with or without multiple minor antigen disparities) allogeneic bone marrow to engraft and establish long-term mixed chimerism in 40 to 82% of recipients in three different strain combinations. The administration of nontolerant donor spleen cells at 5 weeks or at 5, 8, and 11 weeks posttransplant was capable of eliminating host hematopoietic cells, leading to full or nearly full donor chimerism in six of six and two of four chimeric animals in two different strain combinations. No clinical evidence of GVHD was observed in any recipients of these donor leukocyte infusions (DLI). These studies demonstrate that induction of mixed chimerism with nonmyeloablative conditioning followed at appropriate times by DLI might allow lymphohematopoietic GVH reactions, and hence GVL effects, to eliminate chronic hematologic malignancies without causing clinically significant GVHD.
Engraftment of human peripheral blood lymphocytes in normal strains of mice
Blood
Transplantation of bone marrow from SCID mice into lethally irradiated normal mice can potentially endow the normal recipients with characteristics typical of the immune-deficient SCID mouse. In the present study, we investigated whether intraperitoneal grafting of human peripheral blood lymphocytes (PBLs), which has been documented in the SCID mouse, can also be achieved in irradiated BALB/c mice radioprotected with SCID bone marrow. Evaluation of different radiation protocols suggested that, considering the quality of engraftment and rate of survival, optimal results were obtained with split dose total body irradiation (TBI; 4 Gy followed 3 days later by 10 Gy). Monitoring of mouse T cells in peripheral blood indicated an inverse correlation between the presence of such cells and the engraftment of human CD45+ cells in the peritoneum. Also, engraftment of human PBLs in nude BALB/c mice, conditioned with the same radiation protocol, was significantly higher than that achieved in th...
American Journal of Transplantation, 2017
Mixed chimerism is a promising approach to inducing allograft and xenograft tolerance. Mixed allogeneic and xenogeneic chimerism in mouse models induced specific tolerance and global hyporesponsiveness, respectively, of host mouse natural killer (NK) cells. In this study, we investigated whether pig/human mixed chimerism could tolerize human NK cells in a humanized mouse model. Our results showed no impact of induced human NK cell reconstitution on porcine chimerism. NK cells from most pig/human mixed chimeric mice showed either specifically decreased cytotoxicity to pig cells or global hyporesponsiveness in an in vitro cytotoxicity assay. Mixed xenogeneic chimerism did not hamper the maturation of human NK cells but was associated with an alteration in NK cell subset distribution and interferon gamma (IFN-c) production in the bone marrow. In summary, we demonstrate that mixed xenogeneic chimerism induces human NK cell hyporesponsiveness to pig cells. Our results support the use of this approach to inducing xenogeneic tolerance in the clinical setting. However, additional approaches are required to improve the efficacy of tolerance induction while ensuring adequate NK cell functions.
Journal of Experimental Medicine, 1988
Graft-vs.-host (GVH)-related immunosuppression has previously been demonstrated in F1 rodent recipients of parental lymphoid cells, and has been thought to result from an immunologic attack of the donor against the host. Since all cells of such F1 recipients could potentially bear target class I MHC alloantigens, it has not previously been possible to determine precisely the target tissues responsible for development of GVH-related effects. In the present studies we have used mixed allogeneic chimeras as recipients of host or donor-strain lymphocyte inocula, and have made the surprising observation that "GVH-induced" immune unresponsiveness does not require GVH reactivity, per se, but develops in the presence of a one-way alloresponse against lymphohematopoietic cells in either the GVH or the host-versus-graft direction.
Immunology, 2006
Va14i natural killer T cells (NKT cells) are a CD1-restricted subset of NKT cells that express an invariable Va14 + Ja281 + ab T-cell receptor. To determine whether the absence of Va14i NKT cells from the graft affects the development of acute GVHD, we induced GVH reactions using Ja281-/mice as donors in the C57BL/6fi(C57BL/6 • DBA/2)F 1-hybrid strain combination. Recipients of grafts from Ja281-/donors were not protected from either the morbidity or the severe wasting syndrome associated with the development of acute GVHD, but the concentrations of some T helper 1 (Th1) and Th2 cytokines were different from those seen in recipients of grafts from wild-type donors. Interferon-c was seen earlier (day 4) in recipients of grafts from Ja281-/donors but did not reach the concentrations seen in recipients of grafts from wild-type donors on day 8 (P < 0Á02). On day 8, the amount of tumour necrosis factor-a released into the serum following the injection of a small amount of lipopolysaccharide was lower in recipients of grafts from Ja281-/donors (P < 0Á02). The amount of interleukin (IL)-5 was also lower in recipients of grafts from Ja281-/donors, when compared to the concentration seen in recipients of grafts from wild-type donors (P < 0Á002). IL-13 was seen in recipients of grafts from Ja281-/donors but not in recipients of grafts from wild-type donors. Our findings show that the absence of donor Va14i NKT cells is associated with lower concentrations of some Th1 cytokines. We also observed higher IL-13 concentrations and lower IL-5 concentrations in recipients of grafts from Ja281-/donors indicating a variable effect on Th2 cytokine production.
The fate of human peripheral blood lymphocytes after transplantation into SCID mice
European Journal of Immunology, 1993
The fate of human peripheral blood lymphocytes after transplantation into SCID mice* Human peripheral blood lymphocytes (hu-PBL) can be adoptively transferred by intraperitoneal injection into mice with severe combined immunodeficiency (SCID). The transplanted lymphocytes can produce immunoglobulin (Ig), respond to antigens, and survive for months in this chimeric model (hu-PBL SCID). However, whether the lymphocytes actually repopulate and reconstitute lymphoid structures and organs has been subject of some debate. To address this question and to characterize the hu-PBL SCID model better, we employed a novel technique for the identification of human cells in xenogeneic mice.We used fluorescence in situ hybridization (FISH) with a biotinylated DNA probe to all human centromeres. We demonstrated that FISH could be used to detect human cells when they accounted for less than 1 % of humadmouse cell mixtures; it could also be employed for the identification and localization of individual human cells in tissue sections. By using FISH, we studied 31 SCID mice injected with 1.5 x lo7-4 x lo7 hu-PBLviaintravenous (i.v.) or intraperitoneal (i-p.) routes. In the 6 i.v.-injected mice, we found that the human cells were removed from the circulation into the lung within 1 h. In 22 of 25 i.p.-injected animals, 90-3716 pglml of human IgG was found in the sera at 3 to 13 weeks after transplantation (a.t.). Human cells colonized the peritoneal cavity and persisted for up to 13 weeks a.t. and, in the 12 mice studied, accounted for 4 % to 57 % of the cells in the peritoneal fluid. However, only rare, isolated human cells were found in the spleen, blood, bone marrow, lung or Peyer's patches. In 7 of 19 mice that received hu-PBL i.p. from Epstein-Barr virus-seropositive donors, we found masses of human cells usually beneath the peritoneal lining but sometimes infiltrating normal tissue. We conclude that FISH offers a simple means for accurate identification of human cells in the xenogeneic mouse. Although there is colonization of the peritoneal cavity in most mice, and development of lymphoid masses in some, there is no reconstitution of lymphoid structures and only minimal engraftment of lymphoid organs by human cells in conventionallyprepared hu-PBL SCID constructs.