Granulysin expression is a marker for acute rejection and steroid resistance in human renal transplantation

Minnie M. Sarwal; Alkesh Jani; Stella Chang; Phil Huie; Zhuo Wang; Oscar Salvatierra; Carol Clayberger; Richard Sibley; Alan M. Krensky; Martha Pavlakis

doi:10.1016/S0198-8859(00)00228-7

Granulysin expression is a marker for acute rejection and steroid resistance in human renal transplantation

Minnie M. Sarwal^*, Alkesh Jani, Stella Chang, Phil Huie, Zhuo Wang, Oscar Salvatierra, Carol Clayberger, Richard Sibley, Alan M. Krensky, Martha Pavlakis

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

80 Scopus citations

Abstract

Differentiating etiologies of transplant dysfunction without biopsy and optimizing therapy for acute rejection by predicting steroid resistance will reduce patient morbidity. Granulysin is a cytolytic molecule released by CTL and NK cells and coexpressed with effectors of acute allograft rejection, like perforin and granzymes. Granulysin mRNA and protein expression were studied in peripheral blood lymphocytes (PBL; n = 61 total, n = 10 with intercurrent infections) and biopsy tissue from adult and children renal transplant recipients (n = 97) by competitive quantitative-reverse transcriptase-PCR (QC-RT-PCR) and immunohistochemistry. Differences in cell phenotypes were studied in steroid sensitive and resistant acute rejection biopsies. Granulysin was studied in phytohemagglutinin (PHA) stimulated cell lines (donor PBL and CD45RO⁺ T cells) by FACS, Western blotting, and RT-PCR after pretreating with cyclosporine A (CSA), azathioprine, mycophenolic acid, and steroids. Granulysin mRNA was significantly increased in patient PBL and transplant biopsies during acute rejection (p < 0.0001) and infection (p < 0.001). Rejecting biopsies alone (n = 53) had mononuclear cell granulysin staining. Steroid resistant biopsies (n = 25) had denser granulysin staining (>2 cells/high power field) and CD45RO⁺ lymphocytes, when compared with steroid sensitive (n = 28) rejecting tissue. Granulysin levels were unchanged after azathioprine and mycophenolic acid treatment, decreased after treating activated PBL with steroids and cyclosporine A (CSA), and paradoxically, increased (p < 0.05) after treating CD45RO⁺ CTL with CSA. Elevated PBL granulysin is a peripheral marker for acute rejection and infection and dense granulysin staining a tissue marker for steroid resistance. Memory CTL abound in steroid resistant grafts and may have a markedly different response to CSA immunotherapy, suggesting a possible mechanism for steroid resistance.

Original language	English (US)
Pages (from-to)	21-31
Number of pages	11
Journal	Human Immunology
Volume	62
Issue number	1
DOIs	https://doi.org/10.1016/S0198-8859(00)00228-7
State	Published - 2001

Keywords

Acute rejection
Granulysin
Kidney transplant
Noninvasive
Steroid resistance

ASJC Scopus subject areas

Immunology and Allergy
Immunology

Access to Document

10.1016/S0198-8859(00)00228-7

Cite this

@article{5b7b0496763d43fb8d2daf6b35ce3a48,

title = "Granulysin expression is a marker for acute rejection and steroid resistance in human renal transplantation",

abstract = "Differentiating etiologies of transplant dysfunction without biopsy and optimizing therapy for acute rejection by predicting steroid resistance will reduce patient morbidity. Granulysin is a cytolytic molecule released by CTL and NK cells and coexpressed with effectors of acute allograft rejection, like perforin and granzymes. Granulysin mRNA and protein expression were studied in peripheral blood lymphocytes (PBL; n = 61 total, n = 10 with intercurrent infections) and biopsy tissue from adult and children renal transplant recipients (n = 97) by competitive quantitative-reverse transcriptase-PCR (QC-RT-PCR) and immunohistochemistry. Differences in cell phenotypes were studied in steroid sensitive and resistant acute rejection biopsies. Granulysin was studied in phytohemagglutinin (PHA) stimulated cell lines (donor PBL and CD45RO+ T cells) by FACS, Western blotting, and RT-PCR after pretreating with cyclosporine A (CSA), azathioprine, mycophenolic acid, and steroids. Granulysin mRNA was significantly increased in patient PBL and transplant biopsies during acute rejection (p < 0.0001) and infection (p < 0.001). Rejecting biopsies alone (n = 53) had mononuclear cell granulysin staining. Steroid resistant biopsies (n = 25) had denser granulysin staining (>2 cells/high power field) and CD45RO+ lymphocytes, when compared with steroid sensitive (n = 28) rejecting tissue. Granulysin levels were unchanged after azathioprine and mycophenolic acid treatment, decreased after treating activated PBL with steroids and cyclosporine A (CSA), and paradoxically, increased (p < 0.05) after treating CD45RO+ CTL with CSA. Elevated PBL granulysin is a peripheral marker for acute rejection and infection and dense granulysin staining a tissue marker for steroid resistance. Memory CTL abound in steroid resistant grafts and may have a markedly different response to CSA immunotherapy, suggesting a possible mechanism for steroid resistance.",

keywords = "Acute rejection, Granulysin, Kidney transplant, Noninvasive, Steroid resistance",

author = "Sarwal, {Minnie M.} and Alkesh Jani and Stella Chang and Phil Huie and Zhuo Wang and Oscar Salvatierra and Carol Clayberger and Richard Sibley and Krensky, {Alan M.} and Martha Pavlakis",

note = "Funding Information: This work was supported by grants from the NIH (AI43348-02 for AMK and HD33698 for MMS) and the David and Lucille Salter Packard Foundation (MMS). MP received funding from the Satellite Dialysis Corporation.",

year = "2001",

doi = "10.1016/S0198-8859(00)00228-7",

language = "English (US)",

volume = "62",

pages = "21--31",

journal = "Human Immunology",

issn = "0198-8859",

publisher = "Elsevier Inc.",

number = "1",

}

TY - JOUR

T1 - Granulysin expression is a marker for acute rejection and steroid resistance in human renal transplantation

AU - Sarwal, Minnie M.

AU - Jani, Alkesh

AU - Chang, Stella

AU - Huie, Phil

AU - Wang, Zhuo

AU - Salvatierra, Oscar

AU - Clayberger, Carol

AU - Sibley, Richard

AU - Krensky, Alan M.

AU - Pavlakis, Martha

N1 - Funding Information: This work was supported by grants from the NIH (AI43348-02 for AMK and HD33698 for MMS) and the David and Lucille Salter Packard Foundation (MMS). MP received funding from the Satellite Dialysis Corporation.

PY - 2001

Y1 - 2001

N2 - Differentiating etiologies of transplant dysfunction without biopsy and optimizing therapy for acute rejection by predicting steroid resistance will reduce patient morbidity. Granulysin is a cytolytic molecule released by CTL and NK cells and coexpressed with effectors of acute allograft rejection, like perforin and granzymes. Granulysin mRNA and protein expression were studied in peripheral blood lymphocytes (PBL; n = 61 total, n = 10 with intercurrent infections) and biopsy tissue from adult and children renal transplant recipients (n = 97) by competitive quantitative-reverse transcriptase-PCR (QC-RT-PCR) and immunohistochemistry. Differences in cell phenotypes were studied in steroid sensitive and resistant acute rejection biopsies. Granulysin was studied in phytohemagglutinin (PHA) stimulated cell lines (donor PBL and CD45RO+ T cells) by FACS, Western blotting, and RT-PCR after pretreating with cyclosporine A (CSA), azathioprine, mycophenolic acid, and steroids. Granulysin mRNA was significantly increased in patient PBL and transplant biopsies during acute rejection (p < 0.0001) and infection (p < 0.001). Rejecting biopsies alone (n = 53) had mononuclear cell granulysin staining. Steroid resistant biopsies (n = 25) had denser granulysin staining (>2 cells/high power field) and CD45RO+ lymphocytes, when compared with steroid sensitive (n = 28) rejecting tissue. Granulysin levels were unchanged after azathioprine and mycophenolic acid treatment, decreased after treating activated PBL with steroids and cyclosporine A (CSA), and paradoxically, increased (p < 0.05) after treating CD45RO+ CTL with CSA. Elevated PBL granulysin is a peripheral marker for acute rejection and infection and dense granulysin staining a tissue marker for steroid resistance. Memory CTL abound in steroid resistant grafts and may have a markedly different response to CSA immunotherapy, suggesting a possible mechanism for steroid resistance.

AB - Differentiating etiologies of transplant dysfunction without biopsy and optimizing therapy for acute rejection by predicting steroid resistance will reduce patient morbidity. Granulysin is a cytolytic molecule released by CTL and NK cells and coexpressed with effectors of acute allograft rejection, like perforin and granzymes. Granulysin mRNA and protein expression were studied in peripheral blood lymphocytes (PBL; n = 61 total, n = 10 with intercurrent infections) and biopsy tissue from adult and children renal transplant recipients (n = 97) by competitive quantitative-reverse transcriptase-PCR (QC-RT-PCR) and immunohistochemistry. Differences in cell phenotypes were studied in steroid sensitive and resistant acute rejection biopsies. Granulysin was studied in phytohemagglutinin (PHA) stimulated cell lines (donor PBL and CD45RO+ T cells) by FACS, Western blotting, and RT-PCR after pretreating with cyclosporine A (CSA), azathioprine, mycophenolic acid, and steroids. Granulysin mRNA was significantly increased in patient PBL and transplant biopsies during acute rejection (p < 0.0001) and infection (p < 0.001). Rejecting biopsies alone (n = 53) had mononuclear cell granulysin staining. Steroid resistant biopsies (n = 25) had denser granulysin staining (>2 cells/high power field) and CD45RO+ lymphocytes, when compared with steroid sensitive (n = 28) rejecting tissue. Granulysin levels were unchanged after azathioprine and mycophenolic acid treatment, decreased after treating activated PBL with steroids and cyclosporine A (CSA), and paradoxically, increased (p < 0.05) after treating CD45RO+ CTL with CSA. Elevated PBL granulysin is a peripheral marker for acute rejection and infection and dense granulysin staining a tissue marker for steroid resistance. Memory CTL abound in steroid resistant grafts and may have a markedly different response to CSA immunotherapy, suggesting a possible mechanism for steroid resistance.

KW - Acute rejection

KW - Granulysin

KW - Kidney transplant

KW - Noninvasive

KW - Steroid resistance

UR - http://www.scopus.com/inward/record.url?scp=0035116493&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035116493&partnerID=8YFLogxK

U2 - 10.1016/S0198-8859(00)00228-7

DO - 10.1016/S0198-8859(00)00228-7

M3 - Article

C2 - 11165712

AN - SCOPUS:0035116493

SN - 0198-8859

VL - 62

SP - 21

EP - 31

JO - Human Immunology

JF - Human Immunology

IS - 1

ER -

Granulysin expression is a marker for acute rejection and steroid resistance in human renal transplantation

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this