Bone marrow transplantation or stem cell transplantation has become standard treatment for patients with hematological malignant diseases such as acute leukemia, chronic leukemia and refractory non-Hodgkin's lymphoma, which involves the transfer of autologous or allogeneic stem cells depending on the availability of HLA-matched donor. As only 25-30% of patients can have a completely HLA-matched sibling donor, allogeneic stem cell transplantation is the only curative option for most of the patients with hematological malignancies or inherited disorders of hematopoietic system. However, the application of allogeneic stem cell transplantation is restricted by the development of severe graft-versus-host disease (GVHD), which is caused by donor T cells.
Although researches have shown that high depletion of donor T cells eliminates GVHD, the increased chance of viral infection and leukemia relapse results in the un-improved post-transplant mortality and morbidity. As a result, selective depletion of donor's allo-reactive T cells toward the patient has been suggested as a compensation strategy of T cell depleted stem cell transplantation, which is expected to protect the patient from opportunistic infections and shorten the post-graft immunodeficiency without affecting GVHD reduction.
In this dissertation, a complete strategy for safe and efficient hematopoietic stem cell transplantation was studied: first, the donor's T cells were as completely depleted as possible; then, the depleted T cells were stimulated by the patient's white blood cells and depleted. The depletion was achieved by immuno-magnetic separation. Different monoclonal antibody conjugated magnetic particles were utilized.
Based on the experiment results and statistical analysis, it was determined that antiCD3 dynabeads would be employed for T cell depletion in QMS system, by which 4.0 log10 T cell depletion and >99% recovery of CD34+ cells could be achieved for the separation of >108 leukocytes. For alloreactive T cell depletion, since MACS nanobeads were demonstrated to non-specifically connect to the cells and MACS separation system did not have consistent performance, Stemcell Technologies' customized tetrameric antibody and magnetic microparticles were employed alternatively along with DQMS system. Studies are in process to verify the improvement of alloreactivity elimination by employing increased alloreactive antigens in the separation.
|Advisor:||Chalmers, Jeffrey J.|
|Commitee:||Chalmers, Jeffrey J., Lang, James C., Palmer, Andre F., Zborowski, Maciej|
|School:||The Ohio State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Subjects:||Biochemistry, Biomedical engineering, Immunology|
|Keywords:||Allogeneic stem cell transplantation, Immuno-magnetic, T cell depletion|
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