Uremia is accompanied by profound disturbance of the immune response comprising both impaired immune defence and enhanced inflammation. We have shown that this complex picture is explained by profound perturbation of the human transcriptome mediated through the effects of cMyc, SP1 and other transcription factors which markedly down-regulate both innate and adaptive components. The resulting changes in expression of cytokine, chemokine and other genes gradually recover after transplantation though the timing, extent and diversity of recovery vary widely between subjects and may be related to ethnicity, genetic polymorphisms, age, co-morbid disease and prior antigenic exposure. The individual recovery in immune competence is unmapped, however, and is critically important since rapid recovery may be an important risk for AMR, while persistent dysfunction may be a risk factor for viral infection.
The inability to precisely quantitate these immunological changes has been a major impediment to precision care in transplantation, but is gradually yielding to modern molecular methods. We have previously mapped acute cellular rejection (ACR) at the cellular, genomic and proteomic level; we have developed predictive tools, bioinformatics processes for quality assessment, shown the profound distortion of gene expression in organ failure, the rapid activation of inflammatory genes post-surgery, the recovery of chemokine and interleukin expression in the first 3 months post-transplant, the transcriptomic and proteomic signatures of cytoskeletal organization, signal activation and miRNA expression patterns characteristic of ACR in kidney and heart, and have provided computational biomarker pipelines for development of multi-marker bio-signatures.
We have demonstrated the transient appearance of class I and class II DSA after kidney transplantation, the variable relationship of these measures to early graft rejection and the strong relationship to chronic AMR later in the course. And we have developed rigorous quality standards and national programs to detect and avoid pre-formed donor specific IgG antibodies (DSA) that would trigger AMR post-transplant, and finally reported early measures of graft cellular injury by detection of cell-free DNA. But we lack two sets of precise and critical tools to guide patient management: (a) robust measures of global immune competence to quantitate immune suppression and minimize the risk of infection and malignancy, and (b) reliable measures of the specific response to donor antigens to enable intervention before progression to AMR and irreversible graft injury. We will extend our prior studies as outlined below to produce simple, reproducible and quantitative measures for these purposes thatcan be adopted quickly and simply by all transplant programs.