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Arch Hellen Med, 26(1), January-February 2009, 98-106


Rat chronic graft versus host disease (GvHD) analyses with no chronic GvHD system findings

Department of Transfusion and Cell Therapy, Hamamatsu University School of Medicine, Hamamatsu, Japan

OBJECTIVE Clinical and laboratory signs of chronic graft versus host disease (GvHD) were analyzed in an attempt to establish a bone marrow (BM) transplant system with no chronic GvHD.

METHOD Using DA, Lewis and F1 (DAxLewis) hybrid strain rats, DA BM transplantation combined with a piece of DA spleen graft onto an F1 host spleen were performed in F1 hosts pre-injected with the CD2 antibody (Ab). To evaluate immune tolerance, extracellular signal regulated kinase 1 (ERK1) and ZAP70 kinase were blocked transiently at the time of BM transplantation.

RESULTS Although acute rejection and GvHD were avoided in all the F1 hosts, the F1 hosts receiving either ERK1 Ab or ZAP70 kinase Ab began to show chronic GvHD 100 days post-transplant, except for the rats that received neither ERK1 Ab nor ZAP70 kinase Ab. Rebound activation of donor T cell ERK1 or ZAP70 kinase gradually reinforced chronic GvHD, confirmed not only by clinical findings, but also by flow cytometer and immunochemical electron microscope using ZAP70 kinase Ab. Judging from Western blot (WB) results of thrombospondin 1 (TSP 1) and Bcl-2, it was concluded that the BM and spleen of this chronic GvHD were affected more by autophagy than apoptosis. Large Bcl-2 complexes suggested Bcl-2 binding to Beclin (ATG7). Large quantities of TSP 1 were present in the spleen and BM, with hyperplasia of megakaryocytes.

CONCLUSIONS An anergy, no chronic GvHD, was induced by a piece of spleen graft onto the host spleen, but not by transient ERK1 or ZAP70 kinase blockage, in which only partial adaptive tolerance was seen.

Key words: Autophagy, Bcl-2, Bone marrow transplantation, CD2, Chronic graft versus host disease, Rat, Serine/threonine kinase, Spleen graft, Thrombospodin 1, Tolerance .

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