Prevention of acute lung allograft rejection in rat by the janus kinase 3 inhibitor, tyrphostin AG490.
BACKGROUND
Tyrphostin AG490 (AG490) potently and selectively inhibits gammac/Janus kinase 3-dependent signaling pathways, including downstream Stat5a/b activation and subsequent T cell proliferation by alloantigen stimulation. We evaluated the effects of AG490 on acute rat lung allograft rejection.


METHODS
A 7-day course of an intraperitoneal (IP) injection with 10 mg/kg, 15 mg/kg, or 20 mg/kg AG490 was administered to inhibit the rejection of orthotopically transplanted Brown Norway (RT1n) rat lung allografts in Fischer 344 (RT1(1vl)) rat recipients. The progression of allograft rejection was evaluated by X-ray with a semi-quantitative scoring system and was evaluated histologically with a semi-quantitative rejection scoring system for acute lung allograft rejection. Moreover, to determine whether AG490 regulates CD4+ T cell differentiation during acute rejection, flow cytometry was used to investigate Th1 (interferon-gamma) and Th2 (interleukin [IL]-4, IL-10) intracellular cytokine profiles and the CD4+CD25+ T cell population in recipient splenocytes.


RESULTS
Results of radiology and histology confirmed that treatment with AG490 significantly suppressed acute lung allograft rejection. Furthermore, the splenocytes of the AG490-treated recipients had significantly lower production of interferon-gamma and relatively higher production of IL-10, implying that a Th2 shift was induced by AG490. In addition, AG490-treated recipients had a significantly increased population of CD4+CD25+ T cells in their splenocytes on Day 6 after transplantation.


CONCLUSIONS
These findings suggest that treatment with AG490 prevents acute lung allograft rejection in rats. The effects of AG490 may contribute to development of CD4+CD25+ T cells and a Th2 shift of CD4+ T cells.
Higuchi
Takao
T
The Second Department of Surgery, Fukuoka University School of Medicine, Fukuoka, Japan. tshiraishi-ths@umin.ac.jp
Shiraishi
Takeshi
T
Shirakusa
Takayuki
T
Hirayama
Shin
S
Shibaguchi
Hirotomo
H
Kuroki
Motomu
M
Hiratuka
Masafumi
M
Yamamoto
Satoshi
S
Iwasaki
Akinori
A
Kuroki
Masahide
M
D000208:Acute Disease; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D053616:Janus Kinase 3; D016040:Lung Transplantation / Q000276:immunology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D015375:Receptors, Interleukin-2 / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology; D020032:Tyrphostins / Q000008:administration & dosage*
D015704:CD4 Antigens; C507936:Jak3 protein, rat; D047428:Protein Kinase Inhibitors; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D053616:Janus Kinase 3