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 oxygenase-1 (HO-1 or Hsp-32) resulted in the modulation of several immune effector functions. Here we evaluated whether induction of HO-1 after administration of cobalt protoporphyrin (CoPP) can prevent the development of acute graft-versus-host-disease (GVHD).


METHODS
Acute GVHD was initiated by injection of unfractionated spleen cells from C57BL/6 into B6D2/F1 mice.


RESULTS
Administration of CoPP resulted in increased survival: 85% of CoPP-treated animals survived for >100 days compared with only 29% of saline-treated control animals (P<0.05). In contrast, administration of ZnPP, a well-known inhibitor of HO, accelerated GVHD development. The protective effect of CoPP therapy seemed to be caused by immunomodulation of donor cells, because treatment of cell donors prevented development of acute GVHD in 80% of recipients compared with 0% in control animals. Spontaneous lymphocyte proliferation could be measured with splenocytes harvested from animals developing GVHD but not with splenocytes from recipients of CoPP-treated donor cells. CoPP-treatment had no effect on interleukin-2 or interleukin-4 synthesis but inhibited interferon-gamma production. Mice with active GVHD demonstrated a defective lympho-proliferative response to alloantigens or concanavalin A. However, spleen cells isolated from survivors (on day 100) responded normally. Flow cytometric analysis of splenic T cell populations revealed a severe reduction in recipient type (H-2b,d) cells in mice with active GVHD, whereas in protected mice the number of cells remained normal.


CONCLUSIONS
The results from this study confirmed our previous observation that up-regulation of HO-1 activity is associated with down-regulation of several immune effector functions. This resulted in protection from acute GVHD in a parent into F1 mouse model.
Woo
J
J
SangStat, The Transplant Company, Fremont, CA 94555, USA. jwoo@sangstat.com
Iyer
S
S
Mori
N
N
Buelow
R
R
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D004790:Enzyme Induction / Q000187:drug effects; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D051547:Heme Oxygenase-1; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D010641:Phenotype; D011524:Protoporphyrins / Q000627:therapeutic use*; D013154:Spleen / Q000201:enzymology; D019172:Transplantation Conditioning / Q000379:methods*
D008565:Membrane Proteins; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse