CD40 expression on graft infiltrates and parenchymal CD154 (CD40L) induction in human chronic renal allograft rejection.
BACKGROUND
CD40-CD154 (CD40L) costimulatory signaling plays a pivotal role in the effector mechanisms of transplant graft rejection. In animal models, CD40-CD154 blockade induces long-term graft acceptance concurrent with an absence of chronic rejection (CR) lesions. Given the critical importance of CD40-CD154 interactions in the development of chronic transplant allograft rejection, the relevance of in situ CD40 and CD154 expression was assessed in human chronic renal allograft rejection.


METHODS
The expression of CD40, CD154, CD68, and T-cell receptor (TCR)alpha/beta was analyzed by immunohistochemistry. Serial cryostat sections of snap-frozen core renal allograft biopsies were obtained from 30 renal transplant patients. Biopsy specimens received diagnoses of CR (N = 23) according to the Banff classification and were compared with controls (N = 7) consisting of stable allografts and normal kidney tissue.


RESULTS
Striking CD40 staining of graft cellular infiltrates (P = 0.016) was observed in renal allografts with CR compared with controls. The CD40+ cellular infiltrates in CR were predominantly TCR alpha/beta + T cells and some CD68+ macrophages. These findings were contrasted by the low-level CD40 expression detected in glomeruli and tubules of CR and controls. However, glomerular induction of CD154 was observed in CR allografts (P = 0.028) as compared with controls. CD154 immunoreactivity was demonstrated on glomerular endothelial, epithelial, and mesangial cells. Moderate CD154 expression was detected on tubular epithelial cells, and only weak CD154 immunoreactivity was observed on the infiltrates in isolated CR cases.


CONCLUSIONS
In human chronic renal allograft rejection, CD40 is expressed on graft-infiltrating cells of the T cell and macrophage compartments. CD154 expression is induced on glomerular and tubular epithelial cells during CR, demonstrating another novel source of CD154 expression. The data substantiate the potential contributory role of an interaction between CD40+ graft-destructive effector T cells and macrophages with CD154+ renal allograft parenchymal cells in the development of chronic renal allograft rejection.
Gaweco
A S
AS
Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, Illinois, USA. agaweco@luc.edu
Mitchell
B L
BL
Lucas
B A
BA
McClatchey
K D
KD
Van Thiel
D H
DH
D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D019013:CD40 Antigens / Q000096:biosynthesis*; D023201:CD40 Ligand; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D016030:Kidney Transplantation / Q000009:adverse effects; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D019013:CD40 Antigens; D023201:CD40 Ligand; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C067980:CD68 antigen, human; D000097382:CD68 Molecule