- Prof. Rudolphina J.M. ten Berge, Principal Investigator
- Dr Ajda T. Rowshani, Co-Investigator
- Prof. René A.W. van Lier, Research Associate
- Dr E. Eldering, Research Associate
- Prof. J.J. Weening, Research Associate
- Dr S. Florquin, Research Associate
- Prof. J.P. Medema, Research Associate
- Prof. F. Baas, Research Associate
- Dr A. van Kampen, Research Associate
- Prof. A.H. Zwinderman, Research Associate
- Prof. E.C. Hack, Research Associate
- Academical Medical Center, Amsterdam, The Netherlands
- Immunological Injury and Mechanisms of Self Defense in Subclinical Renal Allograft Rejection
Subclinical renal allograft rejection is defined as the presence of granzyme (Gr) positive T cell infiltrate in the graft causing tubulitis which, in contrast to acute rejection, does not lead to acute dysfunction. Subclinical rejection causes chronic allograft nephropathy and long-term graft failure. Two converging theories may explain this clinically silent state of cytotoxicity: one is that the offending T cells don’t execute their cytotoxic potential.
The other theory, which is the main focus of the present proposal, refers to the resistance of kidney graft tubular epithelial cell (TEC) as a key factor.
Recently, we have shown that SERPINB9 expression by TECs is significantly higher in subclinical rejection than in acute rejection. High SERPINB9 expression correlates with the presence of GrB+ T cells. These data point to a protective role of SERPINB9 conferring TECs resistance to injury. SERPINB9 is the only known human serpin specifically inhibiting GrB, the main effector molecule during rejection.
Hypothesis: In subclinical rejection, strong expression of granzyme inhibitors by TECs protects them against T cell-mediated cytotoxicity. Genetic polymorphism may underlie the interindividual differences in expression of protective proteins like SERPINB9 by donor-derived TECs.
Overall aim: to elucidate the role of granzyme inhibitors in subclinical rejection.
Key objectives: to study 1) regulation and cytoprotective function of SERPINB9 in TECs in vitro; 2) expression and regulation of protease inhibitors of the SERPIN family, potentially involved in inhibition of other cytotoxic molecules in TECs in vitro and in allograft biopsies with subclinical rejection, acute rejection or non-rejection; 3) design of a non-invasive diagnostic tool to distinguish subclinical from acute rejection by analysis of mRNA for SERPINB9 and other candidate protease inhibitors in urinary cells; 4) genetic polymorphisms for SERPINB9 by single nucleotide polymorphism analysis of genomic DNA derived from spleen cells of donors belonging to recipients with subclinical, acute and no rejection.
Significance: This proposal will provide new insights into the pathogenesis of subclinical rejection. Identification of new molecular therapeutic targets may lead to new therapies by amplification of naturally occurring mechanisms of defence. Invention of a non-invasive diagnostic tool for acute and subclinical rejection would mean a great improvement in patient care.