Expression of granzyme A and B proteins by cytotoxic lymphocytes involved in acute renal allograft rejection

Abstract

Granzymes A and B are serine-proteinases stored in the granules of activated cytotoxic T-lymphocytes and natural killer (NK) cells. Expression of granzymes in tissues can be used as an activation marker for cytotoxic cells. Using mAbs specific for human granzyme A or B in immunohistochemical staining techniques we investigated expression of granzyme A and B by lymphocytes infiltrating acutely rejected renal allografts. Twelve core needle biopsies were taken from ten different patients during an episode of acute rejection. Eleven biopsies contained high numbers of granzyme A and B positive lymphocytes infiltrating tubular epithelium, and vascular and glomerular structures. In one patient infiltrating lymphocytes did not express granzyme A and only low amounts of granzyme B. No correlation was found between the number of granzyme positive cells and the severity of the rejection as classified by conventional histological criteria. In one tissue specimen from a patient with a renal allograft without signs of rejection, the number of granzyme positive cells was much lower compared to that of the transplant group. In spite of the presence of a marked inflammatory infiltrate, no granzyme positive cells were detected in renal biopsies from patients with various inflammatory, not transplant-related, renal diseases. Phenotypic analysis showed that granzymes A and B were expressed by CD56+ NK cells and CD3+ cells, representing cytotoxic T-lymphocytes. Thus, this study demonstrates that granzyme A and B protein-expressing lymphocytes infiltrate the kidney allografts during an acute cellular rejection but not in several other inflammatory renal diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

“…Consistent with previous reports, staining for granzyme B was localized to leukocytes in the red pulp but was absent in the white pulp (Fig. 1A) (18). There was no staining when normal goat IgG was used in the place of the primary antibody.…”

“…Consistent with previous reports, granzyme B mRNA in the tonsil localized to leukocytes in the interfollicular space but was absent from the cortex of follicles (Fig. 8A) (18). No vessels with advanced atherosclerosis contained sufficient levels of RNA for this procedure (as determined by acridine/orange staining).…”

Expression of the Apoptosis Inhibitor Protease Inhibitor 9 Predicts Clinical Outcome in Vaccinated Patients with Stage III and IV Melanoma

“…The secretory pathway is triggered after exocytosis of ''cytotoxic'' granules containing perforin and several serine proteases, of which granzyme B is essential for rapid DNA fragmentation in the target cell followed by apoptosis (12). Both activated CTLs and NK cells express granzyme B, which can be detected using standard immunohistochemistry using granzyme B -specific antibodies (13) Target cell death can also be induced by members of the tumor necrosis factor family, such as membrane-bound Fas ligand on the cytotoxic lymphocyte that interacts with the receptor Fas on the target cell (14).…”

Downregulation of T cell receptor expression by CD8(+) lymphocytes in kidney allografts.

“…These cells promote injury and lysis of donor cells through the actions of cytotoxic molecules such as granzyme B and perforin (2). Moreover, expression of granzyme B and perforin strongly correlates with acute cellular rejection in transplant biopsies (3)(4)(5), further supporting the critical role of these CD8 ϩ T cell functions in the pathogenesis of rejection. The CD8 ϩ alloreactive T cell recognizes and engages class I antigens, and its effector functions depend on the molecular interaction of the T cell receptor (TCR) 1 with alloantigens expressed on donor cells.…”