Virtually nothing is known regarding the immune events that occur post- transplant in individual transplant patients, despite the fact that fateful immune decisions are made during this period. As a result, about one half of the patients experience acute rejection, while the other half does not. The reasons for this dichotomy are not known. We have devised a series of relatively simple, non-invasive and infrequent clinical tests for the """"""""Dynamic Immune Assessment (DIA)"""""""" Of transplant patients. Via DIA, we will generate a collage of information that defines the host/graft relationship in transplant patients at various times post-transplant, and the relevant transplant condition that help to shape this relationship. To determine how the patient is responding immunologically to the allograft, there will be periodic assessments of donor-reactive humoral and cellular allosensitization. For this purpose, we have developed new ELISA methods to independently detect donor MHC class I-reactive and MHC class II- reactive alloantibodies. We have also devised the transvivo DTH method, which allows for the first time, the direct detection of human T cell allosensitization. Importantly, this test can discriminate between the classical destructive allosensitization that is associated with graft rejection vs. the newly identified protective allosensitization that is associated with graft acceptance. This may help to explain the rejection/acceptance dichotomy. Immunologic information obtained with these tests can then be correlated with numerous clinical outcome indices, including the incidence of acute rejection. It can also be correlated with two other important transplant parameters, cytokine genotype and immediate urine output. Thus, each patient will be cytokine genotyped, using routine PCR methods that identify alleles of key regulatory cytokines, to define their inherent capacity to produce pro-inflammatory (IL2, ILl2, IFNg, TNF) vs. anti- inflammatory (IL4, IL10, TGFb) cytokines. In addition, the initial 24 hour urine output of each renal allograft will be measured as a functional index that summates the impact of all peritransplant insults to the graft (donor brain death and medication', ischemia/reperfusion injury, etc.). In general, studies on Dynamic Immune Assessment constitute the first steps in the development of meaningful post-transplant monitoring strategies, with the ultimate goal of patient-specific immune engineering for allograft acceptance. That the very least, these studies will provide important new insights into the immune processes leading to allograft acceptance or allograft rejection in transplant patients.
| Pelletier, Ronald P; Bickerstaff, Alice A; Adams, Patrick W et al. (2007) Evaluation of immune regulation in transplant patients using the trans vivo delayed type hypersensitivity assay. Hum Immunol 68:514-22 |
| Pelletier, Ronald P; Hennessy, Patrice K; Adams, Patrick W et al. (2002) Clinical significance of MHC-reactive alloantibodies that develop after kidney or kidney-pancreas transplantation. Am J Transplant 2:134-41 |
| Waldman, W J; Bickerstaff, A; Gordillo, G et al. (2001) Inhibition of angiogenesis-related endothelial activity by the experimental immunosuppressive agent leflunomide. Transplantation 72:1578-82 |
