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Y Reisner

Publications and source records attributed to Y Reisner.

At least 73 records · Page 4Linked to original sources
PubMed1993

Systemic lupus erythematosus-related autoantibody production in mice is determined by bone marrow-derived cells.

Experimental systemic lupus erythematosus (SLE) can be induced in mice by immunization with either a human monoclonal anti-DNA antibody bearing the 16/6 idiotype (16/6 Id) or with a mouse monoclonal anti-idiotypic antibody specific for the 16/6 Id. Susceptibility to the induction of experimental SLE is genetically determined but is not linked to the MHC. In the present study we tested the susceptibility of BM chimeras of different donor-host combinations to the induction of SLE and found that high levels of anti-16/6 Id and anti-ssDNA antibodies were induced in BALB/c-->C57BL/6, BALB/c-->BALB/c and normal BALB/c mice as opposed to C57BL/6-->BALB/c chimeras and normal C57BL/6 mice. The low levels of the anti-16/6 Id and anti-ssDNA antibodies produced by C57BL/6-->BALB/c chimeras immunized with the 16/6 fully allogeneic BMT as such chimeras were shown to produce high levels of antibodies to a T cell-dependent antigen (the synthetic polypeptide (Phe,G)-A--L). These results demonstrate that the production of SLE-related autoantibodies is controlled by donor-type BM derived cells and not by host-type cells in the thymic stroma.

Amino Acid Sequence↗
PubMed1993

Enhancement of BM allografting from C57BL/6 'nude' mice into C3H/HeJ recipients by tolerized T cells from (C57BL/6-->C3H/HeJ) and (C3H/HeJ-->C57BL/6) chimeras.

The possible participation of T cells in the promotion of hematopoietic engraftment of BM allografts, as opposed to their potential role in overcoming host-versus-graft reactions, was investigated recently by using (host x donor)F1 T cells devoid of graft-versus-host activity. In the present study, we provide further evidence of this effect by using tolerized thymocytes from established allogeneic chimeras. We show that tolerant mature thymocytes from donor type (C57BL/6-->C3H/HeJ) or host type (C3H/HeJ-->C57BL/6) chimeras are as effective as (donor x host)F1 thymocytes in promoting both short-term and long-term engraftment of C57BL/6-Nu/Nu T cell-depleted BM cells in lethally irradiated C3H/HeJ recipients.

Animals↗
PubMed1992

Enhancement of T-cell-depleted bone marrow allografts in the absence of graft-versus-host disease is mediated by CD8+ CD4- and not by CD8- CD4+ thymocytes.

Transplantation of T-cell-depleted C57BL/6-Nu/Nu ("nude") bone marrow (BM) into C3H/HeJ recipients, conditioned with 8 Gy total body irradiation plus chemotherapy with the myeloablative drug dimethyl myleran, resulted in poor hematopoietic reconstitution 14 days posttransplant, compared with transplantation with T-cell-depleted BM from normal C57BL/6 donors. Hematopoietic reconstitution of "nude" BM could be improved by the addition of (C57BL/6xC3H/HeJ)F1 thymocytes void of graft-versus-host activity. Enhancement of BM allografting by thymocytes is sensitive to low radiation doses (> or = 5.0 Gy) and can be achieved by transplanting the BM 24 hours before the administration of thymocytes. Fractionation of F1 thymocytes by differential agglutination with peanut agglutinin (PNA) and by fluorescence activated cell sorting showed that this hematopoietic enhancing activity is enriched in the unagglutinated (PNA-) thymocyte fraction and is mediated by PNA- CD8+ and not by PNA- CD4+ thymocytes.

Animals↗
PubMed1991

Engraftment and development of human T and B cells in mice after bone marrow transplantation.

A model for human lymphocyte ontogeny has been developed in a normal mouse. Human bone marrow, depleted of mature T and B lymphocytes, and bone marrow from mice with severe combined immunodeficiency were transplanted into lethally irradiated BALB/c mice. Human B and T cells were first detected 2 to 4 months after transplantation and persisted for at least 6 months. Most human thymocytes (30 to 50 percent of total thymocytes) were CD3+CD4+CD8+. Human immunoglobulin was detected in some chimeras, and a human antibody response to dinitrophenol could be generated after primary and secondary immunization.

Animals↗
PubMed1991

A rapid method for obtaining murine bone marrow cells in high yield.

A rapid and efficient method for obtaining murine bone marrow cells is described, which yields up to twice the amount of cells obtained by the conventional method of flushing through the bones. The femoral and tibial bones are partially broken by an Omni-Mixer in the presence of phosphate-buffered saline to allow their bone marrow content to extrude into the liquid suspension. Murine bone marrow cells obtained by this method were found to be more than 95% viable, and their differential counts were comparable to those of bone marrow suspensions obtained by the flushing method. Moreover, no contamination by cells from the bone or other surrounding tissues has been observed. Transplantation of bone marrow, obtained by the new extrusion method and depleted of T cells, resulted in long-term stable chimeras in which the hematopoietic reconstitution was comparable to that found in mice transplanted with bone marrow obtained by the flushing method. This new method for obtaining murine bone marrow cells may serve as a time- and mice-sparing alternative to the conventional flushing method, and may also prove useful in other animal models.

Animals↗
PubMed1990

Induction of donor-type chimerism in murine recipients of bone marrow allografts by different radiation regimens currently used in treatment of leukemia patients.

Three radiation protocols currently used in treatment of leukemia patients before bone marrow transplantation (BMT) were investigated in a murine model (C57BL/6----C3H/HeJ) for BM allograft rejection. These include (a) a single dose of total body irradiation (8.5 Gy TBI delivered at a dose rate of 0.2 Gy/min), (b) fractionated TBI (12 Gy administered in six fractions, 2 Gy twice a day in 3 days, delivered at a dose rate of 0.1 Gy/min, and (c) hyperfractionated TBI (14.4 Gy administered in 12 fractions, 1.2 Gy three times a day in 3 days, delivered at a dose rate of 0.1 Gy/min). Donor-type chimerism 6 to 8 weeks after BMT and hematologic reconstitution on day 12 after BMT found in these groups were compared with results obtained in mice conditioned with 8 Gy TBI delivered at a dose rate of 0.67 Gy/min, routinely used in this murine model. The results in both parameters showed a marked advantage for the single dose 8.5 Gy TBI over all the other treatments. This advantage was found to be equivalent to three- to fourfold increment in the BM inoculum when compared with hyperfractionated radiation, which afforded the least favorable conditions for development of donor-type chimerism. The fractionated radiation protocol was equivalent in its efficacy to results obtained in mice irradiated by single-dose 8 Gy TBI, both of which afforded a smaller but not significant advantage over the hyperfractionated protocol. This model was also used to test the effect of radiation dose rate on the development of donor-type chimerism. A significant enhancement was found after an increase in dose rate from 0.1 to 0.7 Gy/min. Further enhancement could be achieved when the dose rate was increased to 1.3 Gy/min, but survival at this high dose rate was reduced. These results demonstrated indirectly that dose rate affects the expression of host-type pluripotent stem cells, the progeny of which appear 3 to 6 weeks after treatment with 8 Gy TBI delivered at a dose rate of 0.1 Gy/min, but which are eradicated if radiation is delivered at a dose rate of 1.3 Gy/min.

Animals↗
PubMed1990

Enhancement of bone marrow allografts from nude mice into mismatched recipients by T cells void of graft-versus-host activity.

Transplantation of 8 x 10(6) C57BL/6-Nu+/Nu+ (nude) bone marrow cells into C3H/HeJ recipients after conditioning with 8 Gy of total body irradiation has resulted in a markedly higher rate of graft rejection or graft failure compared to that found in recipients of normal C57BL/6 or C57BL/6-Bg+/Bg+ (beige) T-cell-depleted bone marrow. Mixing experiments using different numbers of nude bone marrow cells with or without mature thymocytes (unagglutinated by peanut agglutinin) revealed that engraftment of allogeneic T-cell-depleted bone marrow is T-cell dependent. To ensure engraftment, a large inoculum of nude bone marrow must be supplemented with a trace number of donor T cells, whereas a small bone marrow dose from nude donors requires a much larger number of T cells for engraftment. Marked enhancement of donor type chimerism was also found when F1 thymocytes were added to nude bone marrow cells, indicating that the enhancement of bone marrow engraftment by T cells is not only mediated by alloreactivity against residual host cells but may rather be generated by growth factors, the release of which may require specific interactions between T cells and stem cells or between T cells and bone marrow stroma cells.

Animals↗
PubMed1990

Development of tolerance to donor type and host type H-2 antigens following transplantation of allogeneic bone marrow in mice.

The responsiveness in mixed lymphocyte culture (MLC) against donor, host or third party antigens both in the thymus and in the spleen was studied in allogeneic chimeras at different time intervals post-bone marrow transplantation (BMT), and the results were correlated with the development of host and donor-type cells in the thymus. Three significant findings were revealed by this analysis. (1) Low but significant anti-host responses are present in allogeneic chimeras despite the lack of graft-versus-host disease. The anti-host responses in MLC can initially be detected in the thymus during the first 3 weeks post-transplant. A significant anti-host response can subsequently be detected in the spleen during the second month post-BMT. (2) The MLC anti-host responses are always higher than the anti-donor responses, indicating that new bone marrow-derived cells which arrive in the thymus after BMT may have a more important role in tolerance induction than the thymus epithelium, which is of host origin and cannot be involved in clonal deletion of donor anti-donor responses. (3) A substantial number of residual host-type prothymocytes survives 9.0 Gy total body irradiation, as manifested by their progeny in the thymus, and reaches a maximum number of 26.6 x 10(6) cells on day 15 post-BMT, before being gradually replaced in the thymus by donor-type thymocytes. The host-type thymocytes are tolerant in MLC towards donor-type cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Enhancement by dimethyl myleran of donor type chimerism in murine recipients of bone marrow allografts.

A major problem in using murine models for studies of bone marrow allograft rejection in leukemia patients is the narrow margin in which graft rejection can be analyzed. In mice irradiated with greater than 9 Gy total body irradiation (TBI) rejection is minimal, whereas after administration of 8 Gy TBI, which spares a significant number of clonable T cells, a substantial frequency of host stem cells can also be detected. In current murine models, unlike in humans, bone marrow allograft rejection is generally associated with full autologous hematopoietic reconstitution. In the present study, we investigated the effect of the myeloablative drug dimethyl myleran (DMM) on chimerism status following transplantation of T cell-depleted allogenic bone marrow (using C57BL/6 donors and C3H/HeJ recipients, conditioned with 8 Gy TBI). Donor type chimerism 1 to 2 months post-transplant of 1 to 3 x 10(6) bone marrow cells was markedly enhanced by using DMM one day after TBI and prior to transplantation. Conditioning with cyclophosphamide instead of DMM, in combination with 8 Gy TBI, did not enhance engraftment of donor type cells. Artificial reconstitution of T cells, after conditioning with TBI plus DMM, by adding mature thymocytes, or presensitization with irradiated donor type spleen cells 1 week before TBI and DMM, led to strong graft rejection and consequently to severe anemia. The anti-donor responses in these models were proportional to the number of added T cells and to the number of cells used for presensitization, and they could be neutralized by increasing the bone marrow inoculum. These results demonstrate the potential of DMM to facilitate engraftment in unsensitized mice in which the host stem cells may compete with donor type cells; the use of DMM to create models in which mechanisms of immune rejection can be studied without interference due to stem cell competition; and that bone marrow allograft rejection may be overcome by increasing the bone marrow inoculum in these stringent models.

Animals↗
PubMed1988

Booster irradiation to the spleen following total body irradiation. A new immunosuppressive approach for allogeneic bone marrow transplantation.

Graft rejection presents a major obstacle for transplantation of T cell-depleted bone marrow in HLA-mismatched patients. In a primate model, after conditioning exactly as for leukemia patients, it was shown that over 99% of the residual host clonable T cells are concentrated in the spleen on day 5 after completion of cytoreduction. We have now corroborated these findings in a mouse model. After 9-Gy total body irradiation (TBI), the total number of Thy-1.2+ cells in the spleen reaches a peak between days 3 and 4 after TBI. The T cell population is composed of both L3T4 (helper) and Lyt-2 (suppressor) T cells, the former being the major subpopulation. Specific booster irradiation to the spleen (5 Gy twice) on days 2 and 4 after TBI greatly enhances production of donor-type chimera after transplantation of T cell-depleted allogeneic bone marrow. Similar enhancement can be achieved by splenectomy on day 3 or 4 after TBI but not if splenectomy is performed 1 day before TBI or 1 day after TBI, strengthening the hypothesis that, after lethal TBI in mice, the remaining host T cells migrate from the periphery to the spleen. These results suggest that a delayed booster irradiation to the spleen may be beneficial as an additional immunosuppressive agent in the conditioning of leukemia patients, in order to reduce the incidence of bone marrow allograft rejection.

Animals↗
PubMed1988

The role of bone-marrow transplants after nuclear accidents.

The probability that bone-marrow transplantation will be beneficial after nuclear accidents depends on several factors, including circumstances of the accident, degree of damage in other body systems, and radiation dose. Transplant-related variables, such as donor-recipient histocompatibility and post-transplant immune suppression, are also important. The benefits of transplantation may result from transient or permanent haemopoietic reconstitution. The balance of potential benefits versus risks should be individually calculated for each accident and each patient; generalisations are likely to result in untenable conclusions.

Accidents↗
PubMed1988

Transient engraftment of T cell-depleted allogeneic bone marrow in mice improves survival rate following lethal irradiation.

C3H/HeJ mice were exposed to 8 or 9 Gy total body irradiation prior to transplantation of 1-15 x 10(6) H-2 incompatible T cell-depleted bone marrow cells from C57BL/6 donors. Survival was greatly enhanced compared to irradiated controls, even at the lowest cell doses. Analysis of spleen cells 1-7 weeks post-transplant revealed that recipients of the lowest doses of T cell-depleted bone marrow had only transient engraftment of donor type cells, and that long-term recovery was autologous. This transient engraftment had a marked beneficial effect both on reconstitution of hematopoiesis and on survival.

Animals↗
PubMed1987

Abrogation of bone marrow allograft resistance in mice by increased total body irradiation correlates with eradication of host clonable T cells and alloreactive cytotoxic precursors.

Host-vs-graft activity presents a major obstacle for transplantation of T cell-depleted bone marrow in HLA-mismatched patients. In a primate model, conditioned exactly like leukemia patients, it was shown that residual host clonable T cells, as well as alloreactive cytotoxic precursors, were present in peripheral blood and spleen after completion of cytoreduction. We have now extended this study in a mouse model for allogeneic bone marrow transplantation. C3H/HeJ mice were treated by 9 Gy total body irradiation (TBI), and 24 hr later their spleen cells were cultured in the presence of T cell growth factor and phytohemagglutinin according to the limit dilution procedure. After 7 days of culture the average frequency of clonable cells was 2.5 X 10(-3) compared with 37 X 10(-3) in the spleens of normal mice. The T cell derivation of the growing cells was ascertained by complement-mediated cytotoxicity with anti-Thy-1 as well as with anti-Lyt-2 and anti-Ly-3T4. In parallel, we found that the initial engraftment rate of bone marrow allograft in mice given 9 Gy TBI was lower than that found in recipients of syngeneic marrow. The initial engraftment rate was measured by the number of colony-forming units in the spleen and by splenic uptake of 125IUdR. A slight increase in TBI from 9 Gy to 11 Gy markedly reduced the difference in the number of spleen colony-forming units or the IUdR uptake between recipients of allogeneic and syngeneic bone marrow. This increase in TBI also coincided with eradication of detectable clonable T cells. Moreover, in mice transplanted with T cell-depleted bone marrow after 9 Gy TBI, we also demonstrate that cytotoxicity against donor-type target cells is present in the spleen 10 to 14 days posttransplantation, whereas in mice treated by 11 Gy TBI such alloreactivity could not be detected. These results suggest that resistance to T cell-depleted allogeneic bone marrow in irradiated mice closely correlates with the frequencies of residual host clonable T cells detectable by conventional immunologic assays.

Animals↗
PubMed1986

Graft rejection and graft-versus-host disease: mirror images.

Graft rejection and graft-versus-host disease (GvHD) complicate bone marrow transplantation in animals and man. The likelihood of each correlates with the degree of genetic disparity between donor and recipient. However, instead of a direct relation between graft rejection and GvHD, these events are inversely correlated: in most instances, they are mutually exclusive. A similar, complex relation exists with a third possible event, graft-versus-leukaemia. Attempts to suppress graft rejection or GvHD are likely to increase the reciprocal outcomes unless additional measures are instituted.

Animals↗