![Augmenting the graft-versus-leukaemia effect of allogeneic non-myeloablative transplantation için kapak resmi Augmenting the graft-versus-leukaemia effect of allogeneic non-myeloablative transplantation için kapak resmi](/client/assets/d79c3e4af2b6d196/ctx/images/no_image.png)
Augmenting the graft-versus-leukaemia effect of allogeneic non-myeloablative transplantation
Başlık:
Augmenting the graft-versus-leukaemia effect of allogeneic non-myeloablative transplantation
Yazar:
Ewing, Joanne, author.
ISBN:
9780438043633
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (332 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-08C.
Özet:
Allogeneic transplantation offers the only curative treatment for a number of haematological malignancies. The most significant obstacle to the transplantation of bone marrow across major and minor histocompatibility barriers is graft versus host disease (GVHD). Using a minimally toxic conditioning regimen a state of mixed chimerism may be achieved with donor-host mutual tolerance without causing lethal graft versus host disease. Once this state of tolerance is established, donor leucocyte infusions or allogeneic tumour antigen-specific cytotoxic T-lymphocytes may be employed as adoptive immunotherapy to harness the graft-versus-leukaemia (GVL) effect. The aim of initial experiments was to establish a clinically applicable, minimally toxic model of chimerism across fully MHC-mismatched barriers without the use of monoclonal antibodies or costimulatory blockade. This was achieved using fludarabine as a potent recipient immunosuppressive agent and post-transplant cyclophosphamide to modulate the kinetics of host T-cell recovery allowing development of tolerance in the absence of GVHD. Using C57B1/6 (H-2b) as recipients of Balb/c (H-2d) donor bone marrow the ability to achieve a stable state of multilineage mixed chimerism was demonstrated. Optimisation of the regimen allowed chimerism to be achieved in 80 to 100% of recipients when pre-transplant cyclophosphamide 100mg/kg and fludarabine 200mg/kg was administered with low-dose 4Gy TBI on day-1. Unmanipulated donor marrow cells were administered at a dose of 1.5 x10e7 on day 0 and immunomodulatory cyclophosphamide 200mg/kg was given on day +3 post transplant. This regimen was immunosuppressive but not myeloablative, although there was transient low-level myelosuppression. Minimal toxicity was seen with no evidence of GVHD. This model has been used as a platform to examine the ability to manipulate donor-host chimeric states through chemoprotection of the donor cell compartment using retroviral transduction with both MDR1 and mutant forms of O6-alkylguanine DNA alkyltransferase. Direct transfer of transduced cells was not possible across MHC-mismatch or multiple minor-mismatch barriers using non-myeloablative conditioning. Engraftment of transduced cells was, however, achieved in syngeneic and congenic recipients. Transduced cells could be secondarily transplanted not only to secondary syngeneic hosts but also to non-myeloablatively conditioned MHC-mismatched recipients and this process of 'passage' was used to demonstrate proof of principle for chemoselection to augment allogeneic MHC-mismatched donor chimerism. Further examination of the ability of this approach to augment the alloimmune effect of allogeneic transplantation was undertaken. Allogeneic, donor chemoresistant mixed chimerism was used as a platform in preliminary experiments to examine adoptive immunotherapy approaches in EL4 leukaemia/lymphoma. A detailed analysis of the failure of cells to be transplanted to MHC-mismatched animals directly following cell culture and transduction was also undertaken. The composition of the cultured donor innoculum and the contribution of facilitator T-cells to engraftment were critically assessed and engraftment across reduced donor-host MHC barriers to transplantation was attempted. Homing of cultured, transduced cells to the marrow and spleen of syngeneic and MHC-mismatched mice was examined under different conditioning protocols.
Notlar:
School code: 1543
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(684300.1) | 684300-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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