The Entangled World of Memory T Cells and Implications in Transplantation

Through the effective targeting of the adaptive immune system, solid organ transplantation became a life-saving therapy for organ failure. However, beyond 1 y of transplantation, there is little improvement in transplant outcomes. The adaptive immune response requires the activation of the innate immune system. There are no modalities for the specific targeting of the innate immune system involvement in transplant rejection. However, the recent discovery of innate allorecognition and innate immune memory presents novel targets in transplantation that will increase our understanding of organ rejection and might aid in improving transplant outcomes. In this review, we look at the latest developments in the study of innate allorecognition and innate immune memory in transplantation.

Section: Innate Immune Memory To Allogeneic Nonselfmentioning

confidence: 99%

Innate Allorecognition in Transplantation: Ancient Mechanisms With Modern Impact

Gui,

Al Moussawy,

Sanders

et al. 2023

“…These immune cells directly or indirectly release a large number of inflammatory cytokines and chemokines and cause cytotoxic effects that damage target organs. 1,3,4 The contribution of the different CD4 + T helper (Th) cell subtypes to the pathogenesis and regulation of aGVHD is a central point in current research. 5,6…”

Section: Introductionmentioning

confidence: 99%

Nuclear Matrix-associated Protein SMAR1 Attenuated Acute Graft-versus-host Disease by Targeting JAK-STAT Signaling in CD4+ T Cells

Huang,

Zhang,

Teng

et al. 2023

Background. Acute graft-versus-host disease (aGVHD) mediated by alloreactive T cells remains a serious and life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). The contribution of the different CD4+ T helper cell subtypes to the pathogenesis and regulation of aGVHD is a central point in current research. The specialized effector subsets of T cells that differentiate from naive T cells into mature cells are closely related to scaffold/matrix-associated region-1–binding protein (SMAR1). However, the role of SMAR1 in aGVHD is unclear. Methods. Peripheral blood was collected from the patients with or without aGVHD after allo-HCT. The differences in CD4+ T cells transduced with the SMAR1 lentivirus vector and empty vector were analyzed. A humanized aGVHD mouse model was constructed to evaluate the function of SMAR1 in aGVHD. Results. The expression of SMAR1 was significantly reduced in the CD4+ T cells from aGVHD patients and related to the occurrence of aGVHD. SMAR1 overexpression in human CD4+ T cells regulated CD4+ T-cell subsets differentiation and inflammatory cytokines secretion and inhibited the Janus kinase/signal transducer and activator of transcription pathway. Moreover, SMAR1 changed chromatin accessibility landscapes and affected the binding motifs of key transcription factors regulating T cells. Additionally, upregulation of SMAR1 expression in CD4+ T cells improved the survival and pathology in a humanized aGVHD mouse model. Conclusions. Our results showed that upregulation of SMAR1 regulated the CD4+ T-cell subpopulation and cytokines secretion and improved survival in a humanized aGVHD mouse model by alleviating inflammation. This study provides a promising therapeutic target for aGVHD.

Elevation of Donor-derived Cell-free DNA Before Biopsy-proven Rejection in Kidney Transplant

Bromberg,

Bunnapradist,

Samaniego-Picota

et al. 2024

Background. Standard-of-care biomarkers for renal allograft rejection are lagging indicators, signaling existing organ injury. This precludes early intervention, when immunological cascades leading to rejection are most susceptible. Donor-derived cell-free DNA (dd-cfDNA) shows promise as an early indicator of rejection, allowing earlier and possibly more effective treatment. This analysis was designed to assess this promise using real-world dd-cfDNA testing evidence. Methods. This retrospective analysis of the prospective, observational ProActive registry study (NCT04091984) assessed dd-cfDNA and serum creatinine levels before biopsy in 424 patients with ≥1 dd-cfDNA test (n = 1013) in the 6 mo before biopsy. Results. Of 4667 enrolled patients, 1631 patients had ≥18 mo of follow-up data, of which 424 had a biopsy and were included in this analysis. Twenty-six biopsies showed antibody-mediated rejection (ABMR), 62 showed T cell–mediated rejection, and 336 showed nonrejection; each from a unique patient. dd-cfDNA fractions were significantly elevated 5 mo before ABMR biopsies, and 2 mo before T cell–mediated rejection biopsies, compared with nonrejection biopsies. In contrast, serum creatinine did not discriminate between rejection and nonrejection in advance, or concurrent with biopsy. Among patients with nonrejection biopsies, estimated glomerular filtration rate was significantly lower in cases with ≥2 increased dd-cfDNA results (≥1%), compared with those with 0 or 1 increased dd-cfDNA result. Conclusions. These data indicate that dd-cfDNA is an early indicator of biopsy-proven rejection, especially ABMR, suggesting a greater role for dd-cfDNA in surveillance to identify patients at high risk of ongoing or future rejection, thus requiring closer monitoring, biopsy, or other management changes.