Analysis of immunoglobulin and T-cell receptor gene deficiency in graft rejection by gene expression profiles.
BACKGROUND
Lymphocyte antigen receptors are critical for allograft rejection, but their precise involvement is only partly understood. Some members of the immunoglobulin superfamily (e.g., alphabeta T-cell receptors [TCR]) are known to be crucial for acute allograft rejection, but the role of other members remains poorly defined.


METHODS
In this study, the authors analyzed two poorly understood receptors, TCRgammadelta and B-cell receptors (BCR), in allograft rejection in a murine model of cardiac transplantation. Using ribonuclease protection assays, their approach was a comprehensive analysis of the expression of immune and inflammatory genes. The mice included those with deficiencies of gammadelta TCR or BCR and alymphoid (recombination activating gene [RAG] knockout) mice. Because the RAG mice lack all TCR and BCR, they provide a baseline with which to compare the effects of TCRgammadelta and BCR deficiency.


RESULTS
Graft survival was extended in the TCRgammadelta- and BCR-deficient mice. Furthermore, the authors were able to identify groups of genes modulated by specific receptors. Five and six genes were expressed at lower levels in the BCR- and TCRgammadelta-deficient groups, respectively. The authors also found eight genes that were at higher levels in the TCRgammadelta-deficient group, suggesting that these receptors have both pro- and antirejection effects.


CONCLUSIONS
Overall, the authors' study shows that the individual regulatory effects of these different lymphocyte antigen receptors are distinct. In addition, several genes are identified that are candidates as necessary for rejection. This has crucial implications for developing clinical therapies that target specific mechanisms for prolonging graft survival.
DeFina
Rachel A
RA
Laboratory of Molecular Immunology, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Liang
Yurong
Y
He
Hongzhen
H
Haley
Kathleen J
KJ
Christopher
Kenneth
K
Finn
Patricia W
PW
Perkins
David L
DL
D000704:Analysis of Variance; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D016000:Cluster Analysis; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D017353:Gene Deletion; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D019672:Genes, T-Cell Receptor; D006084:Graft Rejection / Q000235:genetics*; D006085:Graft Survival / Q000235:genetics; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D005810:Multigene Family; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics*
D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D016692:Receptors, Antigen, T-Cell, gamma-delta