4671 Background: Omega-3 has been reported to enhance the effects of some cancer chemotherapeutic agents and to play a role in the immune system as immunoregulator and immunosuppressant. The effect of a diet rich in omega-3 during immunosuppressed states of anticancer treatment and on bone marrow transplantation (BMT) outcome is not well known. Aims: To study the effect of omega-3 on busulfan-cyclophosphamide (Bu-Cy) conditioning regimen. Moreover, to evaluate the effect of omega-3 on the outcome of BMT after Bu-Cy conditioning. Methods: We evaluated the effects of menhadenfish oil (omega-3 rich) on the myeloablative treatment with Bu-Cy as well as on the outcome of BMT in mice compared to the effects of a diet containing corn oil (omega-6 rich) or to standard chow. Animals were divided into three groups, Group 1, Group 2 and Group 3. In all the groups, female BALB/c mice, 8–12 weeks old, were randomly selected to receive a diet enriched with fish oil, a diet enriched with corn oil or standard chow. The mice were fed for two weeks prior to conditioning. Thereafter, all the mice were injected IP with 80 mg/kg busulfan (Bu) for four days (day –7 to day –4) followed by 200 mg/kg cyclophosphamide (Cy) for two days (days –3 and −2). The mice in groups 1 and 2 were killed on day 0 (the proposed day for transplantation) and spleen and femur bone marrow cells were harvested. Organs were analysed with flow cytometry to evaluate the lymphoid and myeloid cells phenotype. Also, regulatory T cell number and function were studied. Mice in Group 3 were transplanted on day 0 with allogeneic bone marrow cells from 8–12 weeks old male C57BL/6 mice (2.0 × 107 bone marrow cells and 3.0 × 107spleen cells). Results: Fish oil-enriched chow significantly suppressed the function (Figure 1) of CD4+CD25+FoxP3+ regulatory T (Treg) cells compared to standard chow and corn oil fed mice at day 0. However, the percentage of FoxP3+ cells was significantly elevated in mice fed corn oil compared to standard chow. In concert with myeloablative chemotherapy, fish oil enhanced the suppressive effect of Bu-Cy on CD11b+ myeloid and CD11c+CD86+ dendritic cell populations in the bone marrow and spleen compared to the other dietary groups. Recipient mice fed fish oil had lower survival after BMT (Figure 2). A higher survival was observed for corn oil-fed recipients, but this survival rate was still inferior to that of recipients fed standard chow. Feeding recipients omega-3 enriched diet was associated with a more pronounced acute graft versus host disease (aGVHD). BM and spleen from mice fed corn oil demonstrated lower chimerism. Conclusion: Fish oil enhances the immunosuppressive effect of the conditioning regimen (Bu-Cy) in mice. BMT recipients fed a diet rich in polyunsaturated fatty acids either have lower engraftment (corn oil) or react with a lethal aGVHD (fish oil) associated with a suppression of Treg cells. These findings may have clinical implications. PUFA supplementation should be reconsidered and caution is advised in patients undergoing stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.
Omega-3 is known to enhance the effects of several chemotherapeutic agents and to exert several immunoregulatory actions In the present study, we evaluated the effects of a 21-day feeding regimen with omega-3-rich fish oil (FO) and its corresponding control, omega-6 rich corn oil (CO), on the BU-CY conditioning and the development of GVHD after BMT in mice. Before conditioning, FO, but not CO, feeding caused a significant attenuation in the number and functionality of splenic FoxP3 þ T regulatory cells (Treg). FO feeding also enhanced the effects of the conditioning through severe depletion of Treg cells in the spleen and CD11b þ myeloid cells in both the BM and spleen. Consequently, FO-fed animals conditioned with BU-CY showed exacerbated GVHD following transplantation with allogeneic BM and splenic cells. In contrast, identical transplantation in CO-fed mice resulted in poor engraftment and body weight loss. Moreover, in standard-fed recipients, BMT with cells from FO-fed donors resulted in moderate GVHD and improved the survival time, whereas BMT with cells from CO-fed donors shortened the survival time and caused anemia. We conclude that food supplements should be considered in patients undergoing BMT and/or chemotherapy treatment.
The Arabian leopard (Panthera pardus nimr) is critically endangered by the International Union for Conservation of Nature, with an effective population of 150-250 across its entire range in the Arabian Peninsula. Isolation and preservation of multipotent mesenchymal stem cells is beneficial both for medical and research purposes. The optimal protocol for collection, handling, culturing and preserving the Arabian leopard mesenchymal stem cells acquired from bone marrow was established. Anesthesia with combination of medetomidine and tiletamine-zozalepam is the safest option even for old animals with concurrent disease including chronic kidney disease.
Introduction: Polyclonal anti-thymocyte globulin (ATG) is mainly used in hematopoietic stem cell transplantation, as a prevention for graft rejection as well as for GVHD. Immunosuppressive properties of ATG have been considered primarily from the depletion of peripheral lymphocytes. However direct or indirect effects of ATG on other immune components still is controversial. In the present study we evaluated the immunopathologic effects of ATG on immune system in a mouse model. Methods Ten to fourteen weeks old BALB/c and C57BL/6 mice, were injected intra- peritoneally or intravenously with different doses of ATG (0.2mg/kg -25mg/kg) at three dosage schedules. Considering bone marrow transplantation as day 0, ATG were given at days -10, -7 and -5 or -7, -5 and -1 or -5, -3 and -1. At day 0, mice were killed; spleen (SP), bone marrow (BM), lymph nodes (LN) and thymus were removed and analyzed for T-, B-, DC, NK-, T-reg and myeloid cells. To evaluate the efficacy of immunosuppressive effect of ATG, a group of BALB/c mice were conditioned using busulfan (Bu) and ATG and compared to a control group of BALB/c conditioned with Bu (80mg/kg) followed by cyclophosphamide (200mg/kg). Both groups transplanted with BM and spleen cells from C57BL/6 and followed for engraftment and/or GVHD. Results The administration of ATG (0.2- 4.5mg/kg) has resulted in an increase in spleen cellularity while in lymph node and thymus a decreased cellularity was observed. We have found that injecting 4.5mg/kg of ATG at day -7, -5 and -3 significantly decreased T-cell population in spleen and LN compare to Bu-Cy conditioning. The ratio CD4/CD8 increased after ATG treatment showing that CD8 cells are six-fold more sensitive to ATG treatment compared to CD4 lymphocyte. Interestingly T-reg cell population increase after ATG at day 0, however, the increment was negatively correlated with the administration time and positively correlated with the dose. ATG treatment has resulted in an increase in B-cell population by two- and three- fold in spleen and lymph nodes, respectively. Moreover, 1.2- to 3.5-fold increase in DCs, NK and myeloid cells was observed in SP and LN. Thymus cellularity and cell phenotype was less affected while BM cellularity was not affected by ATG treatment. No differences in the ATG effect on cellularity or cell phenotype between IP and IV route was observed. Despite the high immunosuppressive effect observed in T-cell population compared to that seen in Bu-Cy conditioning, no chimerism was observed when Cy was substituted with ATG (4.5 – 10 mg/kg). Conclusion No donor chimerism could be obtained using ATG as a single agent up to 25mg/kg. ATG dose and the administration time are important factors affecting the repopulation of residual T-cells in spleen and lymph node that have to be considered in bone marrow transplantation setting.
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