Journal of Clinical and Experimental Transplantation
Open Access

Immune monitoring are often defined as a strategy which assesses immune reactivity by measuring phenotypical, molecular and functional correlates of the system , which together function a guide for clinical decisions.

Upon transplantation, cell sorts of the innate and adaptive system contribute to the event of tolerance or rejection of the foreign graft. Evidence suggests that the patient’s alloresponse depends upon the relative proportion and interaction of inflammatory and anti-inflammatory subpopulations of those cells. This suggests that, for both the innate immune cell compartment also because the adaptive system, pro and anti-inflammatory subsets are described which the balance between them will most likely determine the result after transplantation. Such rejection is promoted by, e.g. donor reactive T helper type 1 (Th1) cells, whereas their activity is regulated by, e.g. interleukin (IL) 10 and reworking protein (TGF)β producing Tregs. Similarly, both pathogenic and regulatory functions are ascribed to B cells, and even plasma cells, but also macrophages.

Thus, it’ll be not sufficient to work out only number, products or function of 1 cell subset, as is usually performed; rather, simultaneous analysis of several immune cell compartments is going to be required. Furthermore, as composition and performance of immune cells are influenced by internal and environmental challenges which could blur immune monitoring results, the creation of repositories from healthy individuals balanced for age and gender are needed. This may allow corrections a minimum of for age and gender within the diagnosis of success or failure in tolerance induction.

Biomarkers of Tolerance and Rejection in Kidney and Liver Transplantation

As mentioned earlier, active tolerance induction has been achieved in transplant patients. Immune monitoring on SOT patients was performed so as to define their immune characteristics and to spot biomarkers for prospective IS weaning trials in stable patients. Thanks to the rarity of operational tolerance, especially in kidney recipients, this has proved to be difficult. Also, it should be borne in mind that it’s ethically challenging to gather biopsies from clinically proven SOT patients in order that, in some cases, subclinical rejections or inflammatory responses during a seemingly tolerant patient can’t be excluded.

In SOT kidney recipients, tolerance signature seems to be dominated by B cells, as elevated levels of B cell related transcripts like CD20, T cell leukemia/lymphoma 1A (TCL1A), membrane spanning 4 domains A1 (MS4A1), immunoglobulin kappa variable 1D 13 (IGKV1D13) in peripheral blood and urine sediments and an overall shift towards naive and transitional B cells and fewer memory B cells 89 are observed in several clinical trials. Interestingly, this B cell signature also allows differentiation between tolerance development and chronic rejection in preclinical transplant models and is displayed by a proportion of rejection free stable patients at 12 months post-transplant.

In contrast, maintenance of tolerance upon liver transplantation seems to involve other mechanisms compared to kidney transplantation, as SOT liver transplant patients were shown to be characterized by increased frequencies of NK cells or γδ T cells, which wasn’t found for SOT kidney patients. Thanks to the complexity of the immune mechanisms involved, it’s highly likely that a group of various biomarkers need to be utilized in detecting the immunological status of liver and kidney patients. Common biomarkers of rejection are described for various solid organ transplantations, but a mutual ‘signature of tolerance’ in several organs has not been found. Thus, the role of cell types that contribute to tolerance seems to differ in liver and kidney transplant recipients. In liver SOT patients, however, increased numbers of CD4+CD25highFoxP3+Tregs, either within the periphery or the graft, have also been described.

With Tregs playing a crucial role for the induction and maintenance of transplant tolerance, it had been only a matter of your time until the transfer of induced/expanded Tregs was tested in patients. Upon first encouraging reports within the setting of allogeneic somatic cell transplantation, trials to check their safety and also efficacy upon solid organ transplantation were initiated. Last year, Todo and colleagues reported on transfer of an ex vivo enriched Treg product, which was generated by a 2 week culture of recipient lymphocytes with irradiated donor cells within the presence of anti-CD80/86 monoclonal antibodies. In seven of 10 treated liver transplant patients IS might be withdrawn successfully until 18 months post-transplant. Although this wasn’t a controlled trial, these results indicate the facility of adoptive Treg therapy.

The only active tolerance induction approach, which has repeatedly succeeded in IS withdrawal in liver and kidney transplant recipients, is that the induction of chimerism by co-transfer of donor stem cells alongside transplantation of the solid organ graft. This mechanism clearly aims at utilizing central tolerance mechanisms and hence elimination of donor reactive effector T-cells. Thus, it’s not surprising that utilizing TCR sequencing and tracking of donor reactive T-cell clones identified before transplantation, Megan Sykes’ group could show that successful tolerance induction is amid a deletion of donor reactive T-cells. There’s still a debate concerning whether persistent chimerism may be a biomarker of successful tolerance induction in such patients. Interestingly, it’s been reported that patients rendered tolerant via chimerism induction also show similar increases in B cell related transcripts as do SOT kidney recipients. Clearly, further investigations are needed to verify this relationship.