Humoral immunity in mice after allogeneic bone marrow transplantation.

摘要

A number of genetic diseases have been treated with hematopoietic stem cell transplantation (HSCT) for decades. In particular, severe combined immune deficiency (SCID) is a primary immune deficiency that results from a number of inherited mutations. Few patients are fortunate enough to have a human leukocyte antigen (HLA)-identical donor, thus many are transplanted with a semi-matched graft. Although stem cell transplantation can be a life saving treatment, in many, reconstruction of the immune system is delayed resulting in high incidences of infectious disease. The delay in immune reconstitution is most apparent in the B cell compartment. Many patients have not exhibited an ability to produce protective antibodies thus requiring long-term immunoglobulin replacement therapy. Improved understanding of the nature of these defects may lead to more efficacious therapies.; In addition to genetic diseases certain malignancies are also being treated with HSCT. Although most patients receive an autologous or HLA-identical graft, a significant population receives a semi-matched transplant. In these patients, delayed B cell reconstitution and function results in substantial non-relapse associated morbidity and mortality. Improvement of B cell immunity may result from enhancing our knowledge of the inferred deficiencies in B cell function.; The goal of this thesis project was to further our understanding of humoral immunity following transplantation with allogeneic bone marrow. Surprisingly, little has been done in mouse models to address the presumed defects in B cell differentiation. The work presented here is among the first to assess the state of humoral competence after BM transplantation. The studies in this thesis revealed a lesion in higher order B cell immunity after in utero transplantation of allogeneic or haploidentical bone marrow in SLID mice. In the case of allogeneic transplant recipients, our results suggested this lesion resulted from inefficient selection of T helper cells, which drive B cell differentiation. We have also shown irradiated adult mice reconstituted with haploidentical BM exhibited normal B cell function. These results are in contrast to human recipients of semi-matched grafts and more work is required to adequately model the human status of humoral function following transplantation.