Lung transplantation is currently the only effective treatment for end stage lung diseases. However, chronic rejection that manifests as obliterative bronehiolitis (OB) is a major cause of late death after transplantation. The incidence of OB ranges from 34% to 65% while the mortality due to OB ranges from 62% to 100%. It has been reported that a low level of bone marrow derived donor cells was present in the tissues of long-surviving recipients of solid organs. Microchimerism was associated with a decrease in OB in lung recipients. Recent clinical data show that donor bone marrow infusion augments microchimerism, and decreases the incidence of OB. The mechanism by which donor bone marrow attenuates the development of OB is unknown. Lack of such knowledge is an important problem because without it, it is unlikely that effective strategies to reduce OB and to improve the survival of lung recipients can be developed. The objective of this grant application is to determine how infusion of donor bone marrow at the time of lung transplant reduces the development of OB in lung recipients. The central hypothesis of this application is that marrow-derived cells of donor origin down-regulate recipient's allo-immune response via infectious tolerance that involves T regulatory cells. We have formulated this hypothesis based on our own novel observation that bone marrow derived donor cells preferentially home to the lung graft. The rationale for the proposed research is that once we understand how recipient's immune response is modulated by donor bone marrow, better strategies to prevent OB can be developed. We plan to test our hypothesis by pursuing the following two specific aims.
In Aim 1, we will demonstrate that donor bone marrow infusion at the time of lung transplantation modulates the recipient's alloimmune response by infectious tolerance that involves T-regulatory cells.
In Aim 2 we will determine whether dendritic cells in the lung grafts, and recipient's peripheral lymphoid tissues of lung-bone marrow recipients are more tolerogeneic than those from lung-alone recipients. The proposed work is innovative, because it capitalizes on our novel findings that bone-marrow derived cells of donor origins preferentially home to the lung graft in recipients receiving donor bone marrow infusion, and that infusion of donor bone marrow reduces the incidence of obliterative bronehiolitis in humans. We expect that the results of the proposed studies will elucidate the mechanism by which microchimerism modulates the recipient's alloimmune. These results will be significant, because they may help designing therapeutic strategies to reduce OB and to prolong the survival of lung and other solid organ recipients. ? ?
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