Cyclophosphamide inhibits the development of diabetes in the diabetes-prone BB rat.
OBJECTIVE
Cyclophosphamide has been shown to augment the diabetic process in NOD mouse and BB rat models of Type I (insulin-dependent) diabetes mellitus. Because cyclophosphamide has, however, been shown to increase immunoregulatory cell activity, we examined if cyclophosphamide treatment increases immunoregulatory cell activity and inhibits the diabetic process in BB rats.


METHODS
The development of insulitis and diabetes was explored in BB rats treated with saline and cyclophosphamide (60 to 175 mg/kg body weight). Subsets of spleen cells were assessed by flow cytometry and cytokine gene expression by RT-PCR. To determine if cyclophosphamide induces immunoregulatory cell activity, the development of diabetes was assessed in BB rats injected with spleen cells from rats treated with saline and cyclophosphamide.


RESULTS
All dosages of cyclophosphamide decreased the development of diabetes. The degree of insulitis was lower in pancreata from 55-day-old rats treated with cyclophosphamide than those from controls. Cyclophosphamide caused no alterations in the numbers of NK cells, T-cell subsets, or RT6.1+ T cells. The adoptive transfer of spleen cells from cyclophosphamide-treated rats to BB rats inhibited the development of diabetes. Cyclophosphamide treatment decreased IL-12, IL-1beta, IL-2, IFN-gamma and TNF-alpha gene expressions in mononuclear spleen cells but IL-4 gene expression increased.


CONCLUSIONS
These findings show that cyclophosphamide treatment decreases the development of diabetes by inhibiting the development of insulitis. This inhibitory action of cyclophosphamide on the diabetic process seems to be mediated by the induction of immunoregulatory cell activity. The suppression of cytokines that promote Thl cell differentiation by cyclophosphamide treatment could also play a part in the diabetes sparing effect of cyclophosphamide.
Sobel
D O
DO
Georgetown University School of Medicine, Washington, District of Columbia, USA.
Ahvazi
B
B
Jun
H S
HS
Chung
Y H
YH
Yoon
J W
JW
D000375:Aging; D000818:Animals; D003520:Cyclophosphamide / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D051381:Rats; D011913:Rats, Inbred BB; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide