Attenuation of lethal graft-versus-host disease by inhibition of nitric oxide synthase.
We have previously demonstrated that administration of the nitric oxide (NO) synthesis inhibitor aminoguanidine (AG) to mice undergoing nonlethal graft-versus-host disease (GVHD) results in less destruction of host tissue and enhanced proliferative responses of splenic lymphocytes. Subsequently, we have determined whether the amelioration of GVHD pathology associated with inhibition of NO synthesis affects survival in a lethal GVHD model. Utilizing a C57BL/6 to C57BL/6xDBA2JF1 model, administration of parental lymph node lymphocytes instead of splenocytes results in 80-90% lethality by week 4 after GVHD induction. Administration of AG resulted in significantly decreased lethality coincident with decreased serum NO2- + NO3- levels. AG therapy had no effect on donor anti-host cytolytic T cell activity, which indicates that destruction of host tissue via this pathway was unaffected by the therapy. Histological evaluation of spleen, small intestine, bone, and mesenteric lymph node did not reveal any difference in the histological correlates of disease in the treated mice. AG increased various hematopoietic indices, including red blood cell count, white blood cell count, and hemoglobin, which indicates that the disruption of hematopoiesis during acute GVHD is mediated in part by NO. In addition, the number of GVHD mice with endogenous bacterial infections in the spleen and liver was significantly decreased in mice receiving AG therapy. These data indicate that NO plays a detrimental role during GVHD that appears to result in decreased hematopoietic indices and concomitant susceptibility to bacterial infection.
Hoffman
R A
RA
Department of Surgery, University of Pittsburgh, Pennsylvania 15261, USA.
Nüssler
N C
NC
Gleixner
S L
SL
Zhang
G
G
Ford
H R
HR
Langrehr
J M
JM
Demetris
A J
AJ
Simmons
R L
RL
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000201:enzymology; D006146:Guanidines / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D013154:Spleen / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D004791:Enzyme Inhibitors; D006146:Guanidines; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; C004479:pimagedine