Alleviation of graft-versus-host disease after conditioning with cobalt-protoporphyrin, an inducer of heme oxygenase-1

Background Recently, we demonstrated that elevated expression of heme oxyge nase-1 (HO-1 or Hsp-32) resulted in the modulation of several immune effect or functions. Here we evaluated whether induction of HO-1 after administrat ion of cobalt protoporphyrin (CoPP) can prevent the development of acute gr aft-versus-host-disease (GVHD), Methods. Acute GVHD was initiated by injection of unfractionated spleen cel ls from C57BL/6 into B6D2/F-1 mice. Results. Administration of CoPP resulted in increased survival: 85% of CoPP -treated animals survived for > 100 days compared with only 29% of saline-t reated control animals (P<0.05), In contrast, administration of ZnPP, a wel l-known inhibitor of HO, accelerated GVHD development. The protective effec t of CoPP therapy seemed to be caused by immunomodulation of donor cells, b ecause treatment of cell donors prevented development of acute GVHD in 80% of recipients compared with 0% in control animals. Spontaneous lymphocyte p roliferation could be measured with splenocytes harvested from animals deve loping GVHD but not with splenocytes from recipients of CoPP-treated donor cells. CoPP-treatment had no effect on interleukin-2 or interleukin-4 synth esis but inhibited interferon-gamma production. Mice with active GVHD demon strated a defective lympho-proliferative response to alloantigens or conana valin A. However, spleen cells isolated from survivors (on day 100) respond ed normally. Flow cytometric analysis of splenic T cell populations reveale d a severe reduction in recipient type (H-2(b,d)) cells in mice with active GVHD, whereas in protected mice the number of cells remained normal. Conclusion. The results from this study confirmed our previous observation that up-regulation of HO-1 activity is associated with down-regulation of s everal immune effector functions. This resulted in protection from acute GV HD in a parent into F-1 mouse model.