Serine proteinase inhibitor-9, an endogenous blocker of granzyme B/perforin lytic pathway, is hyperexpressed during acute rejection of renal allografts

Thangamani Muthukumar, Ruchuang Ding, Darshana Dadhania, Mara Medeiros, Baogui Li, Vijay K. Sharma, Choli Hartono, David Serur, Surya V. Seshan, Hans Dieter Volk, Petra Reinke, Sandip Kapur, Manikkam Suthanthiran

Research output: Contribution to journalArticle

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Abstract

Background. Serine proteinase inhibitor (PI)-9 with a reactive center PI (Glu)-P1′ is a natural antagonist of granzyme B and is expressed in high levels in cytotoxic T lymphocytes (CTL). In view of the role of CTL in acute rejection, we explored the hypothesis that PI-9 would be hyperexpressed during acute rejection. Because PI-9 can protect CTL from its own fatal arsenal and potentially enhance the vitality of CTL, we examined whether PI-9 levels correlate with the severity of rejection as well as predict subsequent graft function. Methods. We obtained 95 urine specimens from 87 renal allograft recipients. RNA was isolated from the urinary cells and mRNA encoding PI-9, granzyme B, or perforin and a constitutively expressed 18S rRNA was measured with the use of real-time quantitative polymerase chain reaction assay, and the level of expression was correlated with allograft status. Results. The levels of PI-9 (P=0.001), granzyme B (P<0.0001), and perforin mRNAs (P<0.0001), but not the levels of 18S rRNA (P=0.54), were higher in the urinary cells from the 29 patients with a biopsy-confirmed acute rejection than in the 58 recipients without acute rejection. PI-9 levels were significantly higher in patients with type II or higher acute rejection changes compared with those with less than type II changes (P=0.01). Furthermore, PI-9 levels predicted subsequent graft function (r=0.43, P=0.01). Conclusions. PI-9 mRNA levels in urinary cells are diagnostic of acute rejection, predict renal allograft histology grade, and predict functional outcome following an acute rejection episode.

Original languageEnglish
Pages (from-to)1565-1570
Number of pages6
JournalTransplantation
Volume75
Issue number9
DOIs
Publication statusPublished - 15 May 2003
Externally publishedYes

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Serine Proteinase Inhibitors
Allografts
Peptide Hydrolases
Kidney
Cytotoxic T-Lymphocytes
Granzymes
Messenger RNA
Transplants
perforin-granzyme B
Perforin
Real-Time Polymerase Chain Reaction
Histology
Urine
RNA
Biopsy

ASJC Scopus subject areas

  • Transplantation

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Serine proteinase inhibitor-9, an endogenous blocker of granzyme B/perforin lytic pathway, is hyperexpressed during acute rejection of renal allografts. / Muthukumar, Thangamani; Ding, Ruchuang; Dadhania, Darshana; Medeiros, Mara; Li, Baogui; Sharma, Vijay K.; Hartono, Choli; Serur, David; Seshan, Surya V.; Volk, Hans Dieter; Reinke, Petra; Kapur, Sandip; Suthanthiran, Manikkam.

In: Transplantation, Vol. 75, No. 9, 15.05.2003, p. 1565-1570.

Research output: Contribution to journalArticle

Muthukumar, T, Ding, R, Dadhania, D, Medeiros, M, Li, B, Sharma, VK, Hartono, C, Serur, D, Seshan, SV, Volk, HD, Reinke, P, Kapur, S & Suthanthiran, M 2003, 'Serine proteinase inhibitor-9, an endogenous blocker of granzyme B/perforin lytic pathway, is hyperexpressed during acute rejection of renal allografts', Transplantation, vol. 75, no. 9, pp. 1565-1570. https://doi.org/10.1097/01.TP.0000058230.91518.2F
Muthukumar, Thangamani ; Ding, Ruchuang ; Dadhania, Darshana ; Medeiros, Mara ; Li, Baogui ; Sharma, Vijay K. ; Hartono, Choli ; Serur, David ; Seshan, Surya V. ; Volk, Hans Dieter ; Reinke, Petra ; Kapur, Sandip ; Suthanthiran, Manikkam. / Serine proteinase inhibitor-9, an endogenous blocker of granzyme B/perforin lytic pathway, is hyperexpressed during acute rejection of renal allografts. In: Transplantation. 2003 ; Vol. 75, No. 9. pp. 1565-1570.
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abstract = "Background. Serine proteinase inhibitor (PI)-9 with a reactive center PI (Glu)-P1′ is a natural antagonist of granzyme B and is expressed in high levels in cytotoxic T lymphocytes (CTL). In view of the role of CTL in acute rejection, we explored the hypothesis that PI-9 would be hyperexpressed during acute rejection. Because PI-9 can protect CTL from its own fatal arsenal and potentially enhance the vitality of CTL, we examined whether PI-9 levels correlate with the severity of rejection as well as predict subsequent graft function. Methods. We obtained 95 urine specimens from 87 renal allograft recipients. RNA was isolated from the urinary cells and mRNA encoding PI-9, granzyme B, or perforin and a constitutively expressed 18S rRNA was measured with the use of real-time quantitative polymerase chain reaction assay, and the level of expression was correlated with allograft status. Results. The levels of PI-9 (P=0.001), granzyme B (P<0.0001), and perforin mRNAs (P<0.0001), but not the levels of 18S rRNA (P=0.54), were higher in the urinary cells from the 29 patients with a biopsy-confirmed acute rejection than in the 58 recipients without acute rejection. PI-9 levels were significantly higher in patients with type II or higher acute rejection changes compared with those with less than type II changes (P=0.01). Furthermore, PI-9 levels predicted subsequent graft function (r=0.43, P=0.01). Conclusions. PI-9 mRNA levels in urinary cells are diagnostic of acute rejection, predict renal allograft histology grade, and predict functional outcome following an acute rejection episode.",
author = "Thangamani Muthukumar and Ruchuang Ding and Darshana Dadhania and Mara Medeiros and Baogui Li and Sharma, {Vijay K.} and Choli Hartono and David Serur and Seshan, {Surya V.} and Volk, {Hans Dieter} and Petra Reinke and Sandip Kapur and Manikkam Suthanthiran",
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T1 - Serine proteinase inhibitor-9, an endogenous blocker of granzyme B/perforin lytic pathway, is hyperexpressed during acute rejection of renal allografts

AU - Muthukumar, Thangamani

AU - Ding, Ruchuang

AU - Dadhania, Darshana

AU - Medeiros, Mara

AU - Li, Baogui

AU - Sharma, Vijay K.

AU - Hartono, Choli

AU - Serur, David

AU - Seshan, Surya V.

AU - Volk, Hans Dieter

AU - Reinke, Petra

AU - Kapur, Sandip

AU - Suthanthiran, Manikkam

PY - 2003/5/15

Y1 - 2003/5/15

N2 - Background. Serine proteinase inhibitor (PI)-9 with a reactive center PI (Glu)-P1′ is a natural antagonist of granzyme B and is expressed in high levels in cytotoxic T lymphocytes (CTL). In view of the role of CTL in acute rejection, we explored the hypothesis that PI-9 would be hyperexpressed during acute rejection. Because PI-9 can protect CTL from its own fatal arsenal and potentially enhance the vitality of CTL, we examined whether PI-9 levels correlate with the severity of rejection as well as predict subsequent graft function. Methods. We obtained 95 urine specimens from 87 renal allograft recipients. RNA was isolated from the urinary cells and mRNA encoding PI-9, granzyme B, or perforin and a constitutively expressed 18S rRNA was measured with the use of real-time quantitative polymerase chain reaction assay, and the level of expression was correlated with allograft status. Results. The levels of PI-9 (P=0.001), granzyme B (P<0.0001), and perforin mRNAs (P<0.0001), but not the levels of 18S rRNA (P=0.54), were higher in the urinary cells from the 29 patients with a biopsy-confirmed acute rejection than in the 58 recipients without acute rejection. PI-9 levels were significantly higher in patients with type II or higher acute rejection changes compared with those with less than type II changes (P=0.01). Furthermore, PI-9 levels predicted subsequent graft function (r=0.43, P=0.01). Conclusions. PI-9 mRNA levels in urinary cells are diagnostic of acute rejection, predict renal allograft histology grade, and predict functional outcome following an acute rejection episode.

AB - Background. Serine proteinase inhibitor (PI)-9 with a reactive center PI (Glu)-P1′ is a natural antagonist of granzyme B and is expressed in high levels in cytotoxic T lymphocytes (CTL). In view of the role of CTL in acute rejection, we explored the hypothesis that PI-9 would be hyperexpressed during acute rejection. Because PI-9 can protect CTL from its own fatal arsenal and potentially enhance the vitality of CTL, we examined whether PI-9 levels correlate with the severity of rejection as well as predict subsequent graft function. Methods. We obtained 95 urine specimens from 87 renal allograft recipients. RNA was isolated from the urinary cells and mRNA encoding PI-9, granzyme B, or perforin and a constitutively expressed 18S rRNA was measured with the use of real-time quantitative polymerase chain reaction assay, and the level of expression was correlated with allograft status. Results. The levels of PI-9 (P=0.001), granzyme B (P<0.0001), and perforin mRNAs (P<0.0001), but not the levels of 18S rRNA (P=0.54), were higher in the urinary cells from the 29 patients with a biopsy-confirmed acute rejection than in the 58 recipients without acute rejection. PI-9 levels were significantly higher in patients with type II or higher acute rejection changes compared with those with less than type II changes (P=0.01). Furthermore, PI-9 levels predicted subsequent graft function (r=0.43, P=0.01). Conclusions. PI-9 mRNA levels in urinary cells are diagnostic of acute rejection, predict renal allograft histology grade, and predict functional outcome following an acute rejection episode.

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