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Lupu M. PhD Dissertation (" Magna Cum Laude" ): Clinical and Experimental Studies of Hematopoietic Cell Transplantation in Dogs. 2006.

Abstract: The thesis “Clinical and Experimental Studies of Hematopoietic Cell Transplantation in Dogs” starts with an overview of the accomplishments over a 50-year period in the field of hematopoietic cell transplantation using the pre-clinical canine model. The hematopoietic cell transplantation methodology currently used in the pre-clinical canine setting is described for the purpose of translation to the veterinary clinical oncology field for the treatment of dogs with hematological malignancies. This is successfully exemplified by a clinical report where we applied the hematopoietic cell transplantation for the treatment of a pet dog with T-cell lymphoma. The novelty of this transplant was the donor search among a multi-generation family, compared to the situation in the research field where matched related donor search is performed among littermates, siblings, offspring and parents. In addition this was the first report when the molecular dog leukocyte antigen typing methods were used for the donor search of a dog with a malignant hematological condition undergoing a hematopoietic cell transplant, compared to the early attempts were dogs with various malignancies given marrow grafts were typed using serological and cellular typing methods.
The experimental part of the thesis describes the attempts to induce muscle regeneration using a stem cell based therapy in a canine model of X-linked muscular dystrophy that closely resembles Duchenne muscular dystrophy in children. The results show that bone marrow cells do not possess the in vivo potential to generate muscle reconstitution in this model, which predicts that this therapy would not be feasible for children with Duchenne muscular dystrophy. The experimental part of the thesis continues with the investigation of the bioavailability and interdose variability of oral micophenolate mofetil, an anti-metabolite immunosuppressive drug that is currently administered in the canine model only subcutaneously. In addition we investigated in this model the effects of prior and concomitant oral nonabsorbable antibiotics on mycophenolic acid, the active metabolite of mycophenolate mofetil, pharmacokinetics. The results suggest that substantial interdose variability after oral mycophenolate mofetil administration occurs even in well-controlled conditions, and provide preliminary data regarding the effects of non-absorbable antibiotics upon enterohepatic circulation of mycophenolic acid, which could be further investigated in patients undergoing hematopoietic cell transplantation.

Keywords: hematopoietic cell transplantation, cell therapy, hematological malignancies, Duchenne muscular dystrophy, stem cell plasticity, immunosuppression, translational research, dog

Posted by Marilena Plesu (Lupu)


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