The relationship of granzyme A and perforin expression to cardiac allograft rejection and dysfunction.
The mechanisms underlying contractile dysfunction following heart transplantation are poorly defined. To investigate the role of cytotoxic T cells (CTL) in cardiac transplant rejection, and during episodic contractile dysfunction, we performed a prospective study analyzing the expression of granzyme A and perforin, two functional markers of activated CTL. Sixteen consecutive patients were analyzed during the first year posttransplantation. All patients received induction therapy with OKT-3 and received standard three-drug immunosuppression therapy. Rejection status was monitored using routine surveillance endomyocardial biopsy and graded according to the ISHLT scale. Granzyme A and perforin mRNA were detected by reverse transcription PCR at the time of each routine biopsy. A total of 64/123 biopsies were positive for granzyme expression, while 38/123 samples were positive for perforin expression. LV function was monitored using M-mode derived fractional shortening and Doppler assessment of diastolic function (isovolumic relaxation time [IVRT] and pressure half-time [P1/2]). As expected, the presence of granzyme A message was associated with rejection score (ANOVA, P = 0.001). In addition, granzyme A expression was correlated with a decrease in diastolic function (chi 2 = 6.4, P < 0.02), but was not associated with systolic function. The presence of perforin message was not correlated with functional changes or with rejection grade, but was associated with granzyme expression (chi 2 = 9.11, P = 0.0025). These studies suggest that the presence of granzyme A message may be an important predictor of graft function.
Alpert
S
S
Division of Cardiovascular Medicine, Stanford University School of Medicine, California 94305, USA.
Lewis
N P
NP
Ross
H
H
Fowler
M
M
Valantine
H A
HA
D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D015415:Biomarkers; D001706:Biopsy; D005260:Female; D015870:Gene Expression; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053804:Granzymes; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011237:Predictive Value of Tests; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous
D015415:Biomarkers; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human