Table 2 Data extraction for immune response modulation-related studies

Bestard et al. [47]

Spain/Germany

R OBS

To confirm that FOXP3-expressing T cells in SCR patients are Treg cells and investigate whether the benefit from FOXP3⁺ Treg cells infiltrates in SCR patients is valid in the long term

Intragraft FOXP3⁺ T cells in SCR patients positively correlated with FOXP3 HoM at TSDR. Worse 5-year GF for SCR patients without FOXP3⁺ T cells infiltrate compared with SCR patients with infiltrate. Patients with SCR and IFTA had the same graft outcome as biopsy-negative patients if a FOXP3⁺ T cells infiltrate was present

Bouvy et al. [48]

Netherlands

P OBS

To assess how depleting and non-depleting induction therapies influence the mechanism of Treg cells homeostasis in KTRs

Repopulation of Treg after rATG and basiliximab therapy is the result of homeostatic proliferation and not of thymopoiesis. With both induction therapies, Treg cells could inhibit allospecific T cells. Only after rATG therapy increased proportions of Helios⁻ methylated FOXP3 Treg cells could be found

Braza et al. [49]

France/Germany

CS OBS

To characterize Tregs in TOL patients

TOL patients mobilized an array of potentially suppressive cells, both regulatory B and T cells. These patients had potent CD4⁺CD45RA⁻FOXP3^hi memory Treg cells with a specific TSDR HoM pattern

Sherston et al. [50]

UK/Germany

CS OBS

To determine whether PBMCs DNAm remains stable over time and identify TSDR-demethylated cells in a cohort of long-term KTRs survivors with and without cSCC

The immune phenotype proved to be stable and may be a valuable biomarker for cSCC identification, especially TSDR HoM lymphocytes, since this study proved that elevated circulating Treg cells levels have been associated with a history of cSCC in both immunosuppressed and non-immunosuppressed individuals

Boer et al. [51]

Netherlands

R OBS

To examine

the influence of variations in DNAm of IFNγ and PD1 in different CD8 + T cell subsets on AR

DNAm of IFNγ and PD1 increased at 3 months after KT in memory CD8 + T cells in KTRs, irrespectively of rejection occurrence, indicating that the KT procedure contributed to these variations. At 12 months, no difference was found

Trojan et al. [52]

Germany

CS OBS

To assess whether KTRs with stable GF possess a certain pattern of Treg cells in the blood that is different from the one of HCs

KTRs with stable GF possessed IFNγ⁺ and IFNγ⁻ Treg cells with stable and unstable FOXP3 expression in the blood coexpressing CD28, HLA-DR, CTLA4, CXCR3, Lselectin, TGFβ, perforin, and FasL that might contribute to the establishment and maintenance of good long-term GF

Trojan et al. [53]

Germany

P OBS

To investigate the absolute cell counts of IFNγ⁺ Treg cells subsets in KTRs with good long-term GF, whether they are mainly tTreg or pTreg and whether their expression of FOXP3 is stable or transient in order to offer clues about in vivo vs. in vitro Treg expansion for therapeutic purposes

KTRs with good long-term GF had comparable levels of IFNγ⁺ Treg cells to HCs. Their IFNγ⁺ and IFNγ⁻ Treg cells subsets showed stable and transient FOXP3 expression. Their IFNγ⁺ and IFNγ⁻ Treg cells were more frequently HrM compared with HCs and their levels of Treg cells subsets with stable and transient FOXP3 expression were increased compared to HCs. No association was found between the levels of methylation and kidney function or previous episodes of AR or infections

Alvarez Salazar et al. [54]

Mexico

INT

To analyze the impact of long-term therapy

with BLT or CsA on the phenotype, suppressive function, and the epigenetic status of the FOXP3 TSDR from peripheral Tregs

of STA KTRs

Circulating Tregs are not solely responsible for tolerance in long-term patients. Only BLT-treated patients have increased cellular population showing FOXP3 HoM that could promote tolerance. Tregs from transplanted patients showed significantly reduced suppressive capacity

Peters et al. [55]

Netherlands

R OBS

To identify KTRs at risk for de novo post-KT

cSCC by studying genome-wide DNAm of T cells

16 DMRs between patients with future cSCC and HC in regulatory genomic regions, 5 of which were stable after transplantation and could have a lasting effect on post-KT cSCC development

Peters et al. [56]

Netherlands

R OBS

To prove that functional differences in circulating T cells represent risk factors in the development of a de novo post-KT cSCC

Different DNAm, transcriptional regulation, and protein expression of SERPINB9 between cSCC and non-cSCC patients, identifying a novel risk factor for post-KT cSCC development and providing mechanistic insight into the role of circulating T cells in cSCC development

Cortés-Hernández et al. [57]

Mexico

INT

To clarify whether an ex vivo expansion of Tregs from patients who underwent long-term immunosuppression may be feasible to be used in their treatment

Expansion of Tregs from long-term BLT-treated patients displayed high suppressive activity after 4 weeks. However, the detected lower level of TSDR HoM may require the use of epigenetic modifying agents to stabilize FOXP3 expression to be considered as a valid treatment

Zhu et al. [58]

China

R OBS

To understand if DNAm patterns are modified after KT and if this alteration could influence the fate of KAs

Methylation modification occurred after KT, involving the mTOR signaling pathway. Higher activity in the case of AR-induced AD

Soyoz et al. [59]

Turkey

P OBS

To understand the expression and epigenetic modifications of IL-2, IL-4, and IFNγ in CD4⁺ T cells of KTRs undergoing AR

Increased expression of IFNγ with changes in the methylation status of the + 128 CpG in CD4⁺ T cells of KTRs undergoing AR

Rodriguez et al. [60]

Spain/UK

CS OBS

To analyze DNAm patterns in KTRs with CR and TOL

DNA methylation changes associated with transplant outcome and TOL associated with different DNAm patterns in genes related to B and T cell function. Patients undergoing CR displayed DNAm pattern alterations on genes related to the ubiquitination pathways