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| Author(s): |
Júlia Teixeira Cottas de Azevedo
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2018-03-02 |
| Examining board members: |
Kelen Cristina Ribeiro Malmegrim de Farias;
Vanderson Geraldo Rocha;
Maria Carolina de Oliveira Rodrigues
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| Advisor: | Kelen Cristina Ribeiro Malmegrim de Farias; Eduardo Antonio Donadi |
| Abstract | |
Sickle cell disease (SCD) is a monogenic disease, one of the most prevalent in the world, caused by one point mutation at position 6 of the ?-globin gene, which results in abnormal production of hemoglobin S. Currently, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option available for patients with SCD. However, few studies have evaluated the mechanisms of action involved in different therapeutic responses of SCD patients treated with allogeneic HSCT. Additionally, although the immune system plays a central role in HSCT, there is no study correlating immune reconstitution patterns with the development of graft versus host disease (GVHD) and graft maintenance in SCD transplanted patients. Thus, in this work, we have evaluated the mechanisms of hematological and immunological reconstitution involved in therapeutic response of SCD patients submitted to allogeneic HSCT. For this purpose, peripheral blood samples from SCD patients treated with HSCT were collected before and at various periods after transplantation (1 month, 3, 6, 12, 24, 36, 48 and 60 months). Then, were have evaluated the: grafting by quantification the nucleated cells chimerism; percentage of hemoglobin; expression of adhesion molecules in erythrocytes and reticulocytes; plasma levels of SCD biomarkers; differential expression of genes associated with inflammatory response; frequencies and absolute numbers of lymphocyte and myeloid subpopulations in peripheral blood; and plasma levels of GVHD biomarkers. The majority of patients maintained mixed chimerism until 5 years after transplantation. Of the 40 patients evaluated, 8 had graft failure, 14 developed acute GVHD (aGVHD) and 6 had chronic GVHD (cGVHD). All patients with acute or chronic GVHD developed mild symptoms of the disease and were easily treated. The chronic inflammatory response, the expression of adhesion molecules on the red cell surface (mature red blood cells and reticulocytes), the reticulocyte frequency and the hemoglobin S percentage were decreased after HSCT. Patients with graft failure had higher frequency of monocytic myeloid-derived suppressor cells (MDSC-M) 1 month after transplantation, higher number of iNKT 3 months after transplantation, lower number of CD8+PD-1+ T cells 12 months after transplantation and lower number of CD8+CD28+CD57+ T cells 24 months after transplantation than grafted patients. Increased numbers of regulatory T cells (CD4+CD25hiGITR+, CD8+CD28-CD57+ and CD8+CD28-FOXP3+ T cells) were also observed after transplantation in grafted patients compared to pre-transplantation period. In addition, patients with aGVHD showed increased levels of IL-15, IL-22, CD25/IL2R?, April, HGF and ST2 after transplantation compared to baseline. Patients with aGVHD had lower numbers of exhausted CD4+PD-1+ and CD8+PD-1+ T cells 1 month after HSCT and higher numbers of iNKT cells 3 months after HSCT than non-GVHD patients. Patients with aGVHD had expansion of MDSC-M and MDSC-G at 1 month after transplantation compared to pre-transplantation period. In conclusion, based on the immunological and hematological evaluations, our study has demonstrated that allogeneic HSCT has therapeutic efficacy in patients with SCD. In addition to significant improvement in the chronic inflammatory condition, SCD patients without GVHD and/or without graft failure showed relevant expansions of regulatory T cells (CD4+CD25hiGITR+T cells, CD8+CD28-CD57+T cells and CD8+CD28+FOXP3+T cells) and exhausted T cells during immunological reconstitution process, suggesting an important role of these cells in establishing sustained immune tolerance state after allogeneic HSCT in these patients. (AU) | |
| FAPESP's process: | 14/00088-8 - Haematological and immunological mechanisms involved in the therapeutic response of patients with sickle cell anemia submitted to allogeneic hematopoietic stem cell transplantation |
| Grantee: | Júlia Teixeira Cottas de Azevedo |
| Support Opportunities: | Scholarships in Brazil - Doctorate |