Correlation of T-Cell Subsets and Hypercholesterolemia of the Donor and Its Association with Acute Graft-versus-Host Disease

  • Monica Magdalena Rivera Franco Stem Cell Transplantation Program, Department of Hematology and Oncology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
  • Eucario León-Rodríguez Stem Cell Transplantation Program, Department of Hematology and Oncology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
  • Diana Gómez-Martín Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Keywords: Tregs; Acute graft-versus-host disease; Hypercholesterolemia; Allogeneic hematopoietic stem cell transplantation

Abstract

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.

References

1. Jaimovich G, MartinezRolon J, Baldomero H, et al. Latin America: the next region for haematopoietic transplant progress. Bone Marrow Transplant. 2017; 52(5):671-677.
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.
Published
2019-10-01
How to Cite
1.
Rivera Franco M, León-Rodríguez E, Gómez-Martín D. Correlation of T-Cell Subsets and Hypercholesterolemia of the Donor and Its Association with Acute Graft-versus-Host Disease. Int J Hematol Oncol Stem Cell Res. 13(4):183-188.
Section
Original Article(s)