Effects of blocking the chemokine receptors, CCR5 and CXCR3, With TAK-779 in a rat small intestinal transplantation model.
BACKGROUND
The effect of blocking lymphocyte chemokine receptors with TAK-779 was investigated using a rat intestinal transplantation model.


METHODS
Dark Agouti rat small intestines were heterotopically transplanted into Lewis rats. The recipients were treated with TAK-779 (10 mg/kg per day) by subcutaneous injection. Graft survival, histologic changes, mixed lymphocyte reaction, and antibody production were examined. Furthermore, expression of the chemokine receptors on the graft-infiltrating lymphocytes in the mesenteric lymph node (MLN) and Peyer's patches (PP) were measured using fluorescence-activated cell sorter analysis.


RESULTS
Average duration of survival was greater for group T (with TAK-779: 9.8+/-1.4) than group A (without TAK-779: 7.0+/-0.6). Histologic findings and immunohistochemistry of the graft were consistent with the prolonged survival in group T. In the fluorescence-activated cell sorter analysis, several CD4+ and CD8+ cells were significantly suppressed in the blood, spleen, and MLN of the recipient and in the PP of the graft on postoperative day (POD) 6, but recovered in recipient spleen and MLN by POD 9. However, double-staining of graft-infiltrating lymphocytes in MLN and PP showed a significant reduction in the numbers of T cells expressing CCR5 and CXCR3 by POD 9. On the other hand, mixed lymphocyte reaction and cytokine production, and the antidonor antibody titer were suppressed on POD 6 but not on POD 9.


CONCLUSIONS
TAK779 diminished not only the number of the graft-infiltrating cells and their expression of CCR5 and CXCR3, but also the total number of recipient T cells that play a role in graft rejection. Further exploration of these effects will provide the novel treatment of the intestinal transplantation.
Xu
Hengjie
H
Department of Molecular Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Firdawes
Sabere
S
Yamamoto
Aki
A
Zhao
Yu
Y
Ihara
Yoshiyuki
Y
Uehara
Shuichiro
S
Matsunami
Katsuyoshi
K
Otsuka
Hideaki
H
Fukuzawa
Masahiro
M
Miyagawa
Shuji
S
D000577:Amides / Q000494:pharmacology*; D000714:Anastomosis, Surgical; D000818:Animals; D065100:CCR5 Receptor Antagonists; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology; D007421:Intestine, Small / Q000473:pathology / Q000637:transplantation*; D007583:Jejunum / Q000473:pathology / Q000637:transplantation; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology; D008297:Male; D010581:Peyer's Patches / Q000502:physiology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors*; D016042:Transplantation, Heterotopic / Q000502:physiology; D014184:Transplantation, Homologous / Q000502:physiology; D014185:Transplantation, Isogeneic / Q000502:physiology
D000577:Amides; D065100:CCR5 Receptor Antagonists; C515189:Cxcr3 protein, rat; D000644:Quaternary Ammonium Compounds; D054367:Receptors, CXCR3; C119369:TAK 779