Correlation of T-Cell Subsets and Hypercholesterolemia of the Donor and Its Association with Acute Graft-versus-Host Disease
Background: Acute graft-versus-host disease (aGVHD) is an important cause of death following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The association between cholesterol and aGVHD was previously described potentially resulting from pro-inflammatory responses associated with hypercholesterolemia. The aim of this study was to correlate T-cell subsets in donor bone marrow (BM) samples with their levels of cholesterol and associate these results with recipients who developed aGVHD and those who did not.
Materials and Methods: A prospective study was performed in 39 donor samples. T-cell subsets were analyzed by flow cytometry.
Results: Eleven (28%) donors had hypercholesterolemia. Donor samples with hypercholesterolemia had less Tregs compared to donors with normal levels of cholesterol (22.69 (IQR=30.6) cells/µL vs 52.62 (IQR=44.68) cells/µL, p=0.04). Among all the cohort, aGVHD was observed in 21%: 36% from donors with hypercholesterolemia versus 14% from donors with normal levels of cholesterol.
Conclusion: As we described the association between hypercholesterolemia and diminished Tregs, our results might suggest that normalizing the levels of total cholesterol in the donor, prior performing allo-HSCT, might be an effective approach to diminish the risk of the receptor to develop aGVHD.
2. Niederwieser D, Baldomero H, Szer J, et al. Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey. Bone Marrow Transplant. 2016; 51(6):778-85.
3. Griffith ML, Savani BN, Boord JB. Dyslipidemia after allogeneic hematopoietic stem cell transplantation: evaluation and management. Blood. 2010; 116(8): 1197-204.
4. Joukhadar R, Chiu K. Severe hypercholesterolemia in patients with graft-vs-host disease affecting the liver after stem cell transplantation. EndocrPract. 2012; 18(1):90-7.
5. Marini BL, Choi SW, Byersdorfer CA, et al. The Treatment of Dyslipidemia in Allogeneic Hematopoietic Stem Cell Transplant Patients. Biol Blood Marrow Transplant. 2015; 21(5):809-820.
6. Nassereddine S, Rafei H, Elbahesh E, et al. Acute Graft Versus Host Disease: A Comprehensive Review. Anticancer Res. 2017; 37(4):1547-1555.
7. Broady R, Levings MK. Graft-versus-host disease: suppression by statins. Nat Med. 2008; 14(11):1155-6.
8. Rotta M, Storer BE, Storb RF, et al. Donor statin treatment protects against severe acute graft-versus-host disease after related allogeneic hematopoietic cell transplantation. Blood. 2010; 115(6): 1288-95.
9. Rotta , Storer BE, Storb R, et al. Impact of recipient statin treatment on graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2010; 16(10): 1463-6.
10. Shimabukuro-Vornhagen A, Liebig T, Bergwelt-Baildon M. Statins inhibit human APC function: implications for the treatment of GVHD. Blood. 2008; 112(4):1544-5.
11. Zeiser R, Youssef S, Baker J, et al. Preemptive HMG-CoA reductase inhibition provides graft-versus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activity. Blood. 2007; 110(13):4588-98.
12. Rivera-Franco MM, León-Rodríguez E, Lastra-German IK, et al. Association of recipient and donor hypercholesterolemia prior allogeneic stem cell transplantation and graft-versus-host disease. Leuk Res. 2018; 72:74-78.
13. Taylor PA, Noelle RJ, Blazar BR. CD4 (+) CD25 (+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J Exp Med. 2001; 193(11): 1311-8.
14. Chen X, Vodanovic-Jankovic S, Johnson B, et al. Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. Blood. 2007; 110(10):3804-13.
15. Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation.Nat Med. 2003; 9(9):1144-50.
16. Fontenot JD, Rasmussen JP, Williams LM, et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005; 22(3):329-41.
17. Rezvani K, Mielke S, Ahmadzadeh M, et al. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood. 2006; 108(4):1291–7.
18. Wolf D, Wolf AM, Fong D, et al. Regulatory T-cells in the graft and the risk of acute graft-versus-host disease after allogeneic stem cell transplantation. Transplantation.2007; 83(8):1107–13.
19. Pabst C, Schirutschke H, Ehninger G, et al. The graft content of donor T cells expressing gamma delta TCR+ and CD4 + foxp3+ predicts the risk of acute graft versus host disease after transplantation of allogeneic peripheral blood stem cells from unrelated donors. Clin Cancer Res.2007; 13(10):2916–22.
20. Nayor M, Ramachandran S. Vasan RS. Recent Update to the US Cholesterol Treatment Guidelines: A Comparison with International Guidelines. Circulation. 2016; 133(18): 1795–1806.
21. Vigorito AC, Campregher PV, Storer BE, et al. Evaluation of NIH consensus criteria for classification of late acute and chronic GVHD. Blood. 2009; 114:702-8.
22. Galgani M, De Rosa V, La Cava A, et al. Role of Metabolism in the Immunobiology of Regulatory T Cells. J Immunol. 2016; 197(7):2567-75.
23. Guasti L, Maresca AM, Schembri L, et al. Relationship between regulatory T cells subsets and lipid profile in dyslipidemic patients: a longitudinal study during atorvastatin treatment. BMC Cardio vasc Disord. 2016; 16:26.
24. Maganto-García E, Tarrio ML, Grabie N, et al. Dynamic changes in regulatory T cells are linked to levels of diet-induced hypercholesterolemia. Circulation. 2011; 124(2):185-95.
25. Aguilar-Salinas CA, Gómez-Pérez FJ, Rull J, et al. Prevalence of dyslipidemias in the Mexican National Health and Nutrition Survey 2006. Salud Publica Mex. 2010; 52 Suppl 1:S44-53.