Regulation of alloimmune Th1 responses by the cyclin-dependent kinase inhibitor p21 following transplantation

Welling, Theodore H.; Lu, Guanyi; Csencsits, Keri L.; Wood, Sherri C.; Jarvinen, Lamis Z.; Bishop, D. Keith

doi:10.1016/j.surg.2007.09.040

Cited by 3 publications

(4 citation statements)

References 51 publications

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“…Balomenos et al, reported that p21 is an important regulator of T cell proliferation, demonstrating that p21 null CD4+ and CD8+ T cells proliferated more rapidly than WT T cells under conditions of prolonged stimulation, and furthermore, deletion of p21 promoted cell cycle progression from G 0 G 1 to S phase (28). Knockout of p21 in T cells exacerbated alloreactivity and cardiac graft rejection, while overexpression of p21 inhibited allograft rejection (29), highlighting the importance of p21 in regulating alloreactive T cells. Interestingly, this phenotype is only observed in vivo, but not in vitro (28, 29).…”

Section: Discussionmentioning

confidence: 99%

“…Knockout of p21 in T cells exacerbated alloreactivity and cardiac graft rejection, while overexpression of p21 inhibited allograft rejection (29), highlighting the importance of p21 in regulating alloreactive T cells. Interestingly, this phenotype is only observed in vivo, but not in vitro (28, 29). We found that p21 is upregulated in Teffs populations, but not in Tregs after treatment with AzaC, and that p21-/- Teffs are less sensitive to the antiproliferative effects of AzaC than WT Teffs.…”

Section: Discussionmentioning

confidence: 99%

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Azacitidine Mitigates Graft-versus-Host Disease via Differential Effects on the Proliferation of T Effectors and Natural Regulatory T Cells In Vivo

Cooper

Choi

Karpova

et al. 2017

The Journal of Immunology

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Azacitidine (AzaC) mitigates Graft vs. Host Disease (GvHD) in both murine preclinical transplant models and in human clinical trials while maintaining a robust Graft vs. Leukemia (GvL) effect. Previous studies have failed to investigate the role of natural Tregs on the mitigation of GvHD by AzaC; instead focusing on the generation of suppressive regulatory T cells (Tregs, CD4+CD25+FOXP3+) through the in vivo conversion of alloreactive donor T effectors (Teff CD4+ CD25-, FOXP3-) and the direct anti-proliferative effects of AzaC on allogeneic T cells. Using B6.Foxp3DTR/GFP mice in which Tregs can be specifically ablated through administration of Diphtheria toxin, we demonstrate that nTregs are required in the donor graft for AzaC to optimally protect against GvHD and that nTregs, unlike T effs (Teffs, CD3+FOXP3-), are resistant to the anti-proliferative effects of AzaC. Gene expression analysis identified the potent cell cycle inhibitor, p21, was significantly upregulated in Teffs but not nTregs after treatment with AzaC. Furthermore, we demonstrate that Teffs deficient in p21 are less sensitive to the antiproliferative effects of AzaC. These results, demonstrate that nTregs are essential for AzaC to fully protect against GvHD and have important clinical implications for future clinical trials testing AzaC as a novel method of GvHD prophylaxis in man.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Azacitidine Mitigates Graft-versus-Host Disease via Differential Effects on the Proliferation of T Effectors and Natural Regulatory T Cells In Vivo

Cooper

Choi

Karpova

et al. 2017

The Journal of Immunology

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“…This included a highly significant increase in the expression of the cyclin-dependent kinase inhibitor p21 Cip1 , which plays a critical role in the inhibition of transplant-induced T-cell activation, cell-mediated rejection, and the development of allograft vasculopathy ( Supplementary Fig. S14 ) [49] , [50] , [51] . Furthermore, both interferon alpha/beta signaling and interferon gamma were amongst the top enriched downregulated pathways ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Immunoengineered MXene nanosystem for mitigation of alloantigen presentation and prevention of transplant vasculopathy

et al. 2023

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“…26,27 Briefly, splenocytes from Balb/c mice were irradiated and used as stimulators at a concentration of 4 × 10 6 /mL in RPMI/2% fetal calf serum for ELISPOT. Three sets of responder cells were evaluated: (1) spleen, (2) pooled contralateral inguinal/axillary nodes, and (3) pooled ipsilateral popliteal/inguinal nodes (mice without LN excision only).…”

Section: Methodsmentioning

confidence: 99%

Engendering Allograft Ignorance in a Mouse Model of Allogeneic Skin Transplantation to the Distal Hind Limb

et al. 2015

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Objective The aim of this study was to demonstrate lymphatic isolation in a model of hind limb lymph node (LN) excision, consisting of ipsilateral popliteal and inguinal LN excision and to evaluate the immunologic response to allogeneic skin transplanted onto this region of lymphatic isolation. Methods To study lymphatic flow, C57BL/6 mice underwent lymphadenectomy (n = 5), sham lymphadenectomy (n = 5), or no intervention (n = 5), followed by methylene blue injection. Mice were dissected to determine whether methylene blue traveled to the iliac LN. To study host response to skin transplantation, C57BL/6 mice underwent allogeneic skin transplantation with LN excision (n = 6), allogeneic skin transplantation alone (n = 6), or syngeneic skin transplantation (n = 4). Skin grafts were placed distal to the popliteal fossa and mice were euthanized at day 10. Grafts were stained for endothelial cell and proliferation markers (CD31 and Ki67, respectively). Secondary lymphoid tissues (spleen, ipsilateral axillary LN, and contralateral inguinal LN) were removed and rechallenged with BALB/c alloantigen in vitro with subsequent assay of interferon-γ and interleukin 4 cell expression using ELISPOT technique. Results Mice that underwent LN excision had no evidence of methylene blue in the iliac nodes; mice without surgical intervention or with sham LN excision consistently had methylene blue visible in the ipsilateral iliac nodes. Mice treated with allogeneic skin transplantation and LN excision had lower expression of interferon-γ and interleukin 4 in the secondary lymphoid tissues. Conclusions Lymph node excision completely interrupts lymphatic flow of the hind limb. This model of lymphatic isolation impairs the ability of the transplant recipient to acutely mount a Th1 or Th2 response to allogeneic skin transplants.

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Regulation of alloimmune Th1 responses by the cyclin-dependent kinase inhibitor p21 following transplantation

Cited by 3 publications

References 51 publications

Azacitidine Mitigates Graft-versus-Host Disease via Differential Effects on the Proliferation of T Effectors and Natural Regulatory T Cells In Vivo

Azacitidine Mitigates Graft-versus-Host Disease via Differential Effects on the Proliferation of T Effectors and Natural Regulatory T Cells In Vivo

Immunoengineered MXene nanosystem for mitigation of alloantigen presentation and prevention of transplant vasculopathy

Engendering Allograft Ignorance in a Mouse Model of Allogeneic Skin Transplantation to the Distal Hind Limb

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