Chronic graft loss. Immunological and non-immunological factors

Late loss of kidney grafts is an ongoing problem in the field of transplantation. This is caused by immunological and non-immunological factors, the main immunological driver of rejection is the immune response against HLA molecules that differ between donor and recipient.

To measure the anti-donor responses that a recipient can mount, we have been quantifying anti-donor T-cell frequencies in recipients of renal transplants for several years. Anti-donor direct and indirect pathway frequencies have been measured in vitro in kidney and heart transplant patients by Limiting dilution analysis and other methods. Further, to elucidate the role of CD4+CD25+ regulatory T-cells, these cells have been depleted in ex vivo assays of cellular function. Antigen specific CD4+CD25+ cell lines are being expanded in vitro with a view to using them in immunotherapeutic strategies.

Frequencies of T-cells with direct pathway anti-donor specificity decline in most patients, while those with indirect anti-donor specificity increase in frequency in patients with late graft failure. In keeping with results from experimental models of transplantation tolerance, evidence for allospecific regulatory cells was found in some patients with good, stable transplant function. Interestingly, the regulatory cells appeared to have indirect allospecificity, and no evidence of direct pathway regulation was observed.

The indirect pathway anti-donor alloresponse poses the major threat to long-term transplant survival. Indirect pathway regulatory T-cells arise in some patients. These data are consistent with the hypothesis that tolerance strategies require shrinkage of the direct, and regulation of the indirect, anti-donor response.