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2020, Number 1

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Revista Habanera de Ciencias Médicas 2020; 19 (1)

Evaluation of experimental immunotherapeutic formulations in the hybrid murine model of Graft-versus-Host Reaction

Hong YL, Tamargo SB, Infante BJF, Oliva HR, Fariñas MM, Fuentes MD, Sierra GVG

Language: Spanish
References: 38
Page: 10-29
PDF size: 1039.63 Kb.


ABSTRACT

Introduction: Graft-versus-host disease is the most frequent complication of Hematopoietic Stem Cell Transplants and all transplants containing allogeneic immunocompetent cells; 100% of patients suffer from this complication and about 30% die for this particular cause. A high proportion of cases are steroid-refractory; likewise, other modern immunosuppressive measures fail. In the fields of Immunotherapy and Vaccinology, there is also a worrying shortage of powerful, effective, safe and broad spectrum immunomodulators of biological origin. There is a hybrid murine model of great methodological utility for experimental studies.
Objective: To evaluate two novel formulations of biotechnological origin: an immunopotentiator formulation and an immunosuppressive one, which were developed as cochleates.
Material and Methods: The formulations assayed by Electron Microscopy and RT-PCR were characterized as nanoparticles and for their capacity to regulate lymphokine mRNA expression profile, respectively. The immunomodulatory character was evaluated in vivo using Graft-versus-host disease in (CBAxC57BL) F1 hybrid mice.
Results: Starting from the proteoliposomes derived from Neisseria meningitides, two cochleate formulations were obtained, both with particle diameters below 100 nm. Formulation 1 showed a proinflammatory profile with potent capacity to increase IFNγ and TNFα, and potentiated the Spleen Index up to 2.05 in the GVDH model with p = 0.0002. Formulation 2 showed a suppressor/regulatory profile with potent capacity to increase IL-10 and TGFβ and suppress the production of TNFα. In the model used, this formulation suppressed the Spleen Index in a dose-dependent manner with high statistical significance. The known safety profile and absence of reactogenicity of both formulations was corroborated.
Conclusions: Both formulations have potential application in the fields of GVHD therapy and other pathologies as well as in Vaccinology. The results obtained in the present work suggest the usefulness to continue with the pharmaceutical development and complete the preclinical studies of both formulations.


REFERENCES

  1. Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature [Internet]. 2001 [Citado 24/06/2029]; 411, 385– 389 Disponible en: https://doi.org/10.1038/35077251

  2. Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol [Internet]. 2007[Citado 24/06/2029]; 25:139–70. Disponible en: https://doi:10.1146/annurev.immunol.25.02210 6.141606

  3. Ferrara JL, Reddy P. Pathophysiology of graftversus- host disease. Semin Hematol [Internet]. 2006 [Citado 24/06/2029];43(1):3-10. Disponible en: https://doi:10.1053/j.seminhematol.2005.09.00 1

  4. Zhang L, Chu J, Yu J, Wei W. Cellular and molecular mechanisms in graft-versus-host disease. J Leukoc Biol (2016) J Leukoc Biol [Internet]. 2016 [Citado 24/06/2029];99(2):279- 87. Disponible en: https://doi:10.1189/jlb.4RU0615-254RR

  5. Deeg HJ. How I treat refractory acute GVHD. Blood [Internet]. 2007[Citado 24/06/2029];109:4119-26. Disponible en: https://doi:10.1182/blood-2006-12-041889

  6. Lee SJ. New approaches for preventing and treating chronic graft-versus-host disease. Blood [Internet].2005 [Citado 24/06/2029]; 105:4200- 06. Disponible en: https://doi:10.1182/blood- 2004-10-4023

  7. Kröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, et al. Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease. N Engl J Med. 2016;374(1):43.

  8. Jung JW, Lee YJ, Yoon SCl. Long-term result of maintenance treatment with tacrolimus ointment in chronic ocular graft-versus-host disease. Am J Ophthalmol 2015;159:519.

  9. Neumann T, Schneidewind L, Weigel M, Plis A, VaizianR, Schmidt CA, Krüger W. Ruxolitinib for Therapy of Graft-versus-Host Disease. BioMed Research International [Internet].2019[Citado 24/06/2029]; 1-5. Disponible en: en: http://doi.org/10.1155/2019/8163780

  10. Koreth J, Kim HT, Jones KT, et al. Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versushost disease. Blood 2016; 128:130.

  11. Zhang L, Yu J, Wei W. Advance in Targeted Immunotherapy for Graft-Versus-Host Disease. Front Immunol [Internet]. 2018 [Citado 24/06/2029] 16;9:1087. Disponible en: http://doi:10.3389/fimmu.2018.01087

  12. Schroeder MA, DiPersio JF. Mouse models of graft-versus-host disease: advances and limitations. Dis Model Mech [Internet]. 2011 [Citado 24/06/2029]; 4(3): 318–33. Disponible en: http://doi:10.1242/dmm.006668. 10.1242/dmm.006668

  13. Niederwieser D, Baldomero H, Szer J, Gratwohl M, Aljurf M, Atsuta Y, 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 [Internet]. 2016 [Citado 24/06/2029]; 51(6):778-85. Disponible en: http://doi:10.1038/bmt.2016.18

  14. Arai S, Pidala J, Pusic I. A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation. Clin Cancer Res. 2016; 22:319.

  15. Rodrigues KS, Oliveira-Ribeiro C, Fiuza- Gomes SA, Knobler R, Cutaneous Graft-Versus- Host Disease: Diagnosis and Treatment. Am J Clin Dermatol [Internet]. 2018[Citado 24/06/2029]; 19(1): 33–50. Disponible en: http://doi:10.1007/s40257-017-0306-9

  16. Hill LQ, Alousi A, Kebriaei P, Mehta R, Rezvani K, Shpall E. New and emerging therapies for acute and chronic graft versus host disease. Ther Adv Hematol [Internet]. 2018 [Citado 24/06/2029]; 9(1): 21–46. Disponible en: http://doi:10.1177/2040620717741860

  17. Sierra GVG, Tamargo SB. Adjuvantes inmunológicos para vacunas humanas; estado actual, tendencias mundiales y en Cuba. Revista Anales de la Academia de Ciencias de Cuba.2011;(2):1-32.

  18. Campa C, Sierra VG, Gutiérrez MM, Bisset G, García L, Puentes G, et al. Method for obtaining a vaccine with wide protective range against group B Neisseria meningitidis, the resulting vaccine, gammaglobulin and transfer factor. European Patent [Internet]. EP 0301992; 1995[Citado 24/06/2029]. Disponible en: https://patentimages.storage.googleapis.com/2 a/67/0a/86991ddd224929/EP0301992A2.pdf

  19. Sierra GVG. Cuban Meningococcal Vaccine VA-MENGOC-BC: 30 Years of Use and Future Potential. MEDICC Review. 2019; 21(4):19-27.

  20. Tamargo SB. Nueva generación de adyuvantes nanoparticulados para vacunas profilácticas y terapéuticas de aplicación mucosal y sistémica. [Tesis Doctoral]. La Habana: UMH-ICBP V de Girón, Instituto Finlay, IFAL-UH. Repositorio de Tesis Doctorales CNGC;2012:1- 120.

  21. Santos BT, Pérez CF, Infante B JF, Márquez NY, Ramírez GW, Bourg V, et al. Remote induction of cellular immune response in mice by antimeningococcal nanocochleatesnanoproteoliposomes. Science of the Total Environment [Internet]. 2019[Citado 24/06/2029];668:1055-63. Disponible en: http://doi.org/10.1016/j.scitotenv.2019.03.075

  22. Tamargo B, Márquez Y, Ramírez W, Cedré B, Fresno M, Sierra G. New proteoliposome vaccine formulation from N. meningitidis serogroup B, without aluminum hydroxide, retains its antimeningococcal protectogenic potential as well as Th-1 adjuvant capacity. BMC Immunology. [Internet] 2013[Citado 24/06/2029], 14(Suppl 1):S12:1-5. Disponible en: http://www.biomedcentral.com/1471- 2172/14/S1/S12.

  23. Fernandez-Botran R, Větvička V. Methods in cellular immunology. USA: CRC; 2001.

  24. Chomczynski P, Sacchi N. Single-step RNA isolation from cultured cells or tissues. Anal Biochem [Internet].1987[Citado 24/06/2029];162:156-259. Disponible en: http://doi:10.1016/0003-2697(87)90021-2.

  25. Cohen JL, Trenado A,Vasey D, Klatzmann D, and Salomon, BL. CD4+CD25+ Immunoregulatory T Cells. New Therapeutics for Graft-Versus-Host Disease. J Exp Med [Internet]. 2002 [Citado 24/06/2029]; 196(3): 401–6. Disponible en: http://doi:10.1084/jem.20020090

  26. Villafañe MJ, Moreno LH, Enfermedad Injerto versus Huésped. Dermatol Peru. 2012; 22 (4):161-70.

  27. Zhang L, Yu J and Wei W. Advance in Targeted immunotherapy for Graft-Versus-Host Disease. Front L Immunol [Internet].2018[Citado 24/06/2029]; 9:1087. Disponible en: http://doi:10.33891fimmu.2018.01087

  28. Hannon M, Lechanteur C, Lucas S, Somja J, Seidel L, Belle L, et al. Infusion of clinical grade enriched regulatory T cells delays experimental xenogeneic graft versus-host disease. Transfusion. 2014; 54: 353–63.

  29. Malard F, Bossard C, Brissot E, Chevallier P, Guillaume T, Delaunay J. Increased Th17/Treg ratio in chronic liver GVHD. Bone Marrow Transplant. 2014;49:539-44.

  30. Sharma S. Natural killer cells and regulatory T cells in earlypregnancy loss. Int J Dev Biol. 2014; 58:219–29.

  31. Choi SW, Stiff P, Cooke K, Ferrara JL, Braun T, Kitko C, et al. TNF-inhibition with Etanercept for graft-versus-host disease prevention in high-risk HCT: lower TNFR1 levels correlate with better outcomes. Biol Blood Marrow Transplant. 2012;18:1525-32.

  32. Ghadially H, Ohana M, Elboim M, Gazit R, Gur C, Nagler A,et al. NK cell receptor NKp46 regulates graft-versushost disease. Cell Reports.2014; 7: 1809–14.

  33. Nalle SC, Kwak HA, Edelblum KL, Joseph NE, Singh G., Khramtsova GF, et al. Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease. Sci Transl Med. 2014; 6:243-87.

  34. Verneris MR. Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL. Hematology Am Soc Hematol Educ Program [Internet]. 2013[Citado 24/06/2029];335:41. Disponible en: http://doi:10.1182/asheducation-2013.1.335

  35. Reichenbach DK, Schwarze V, Matta BM. The IL-33/ST2 axis augments effector T-cell responses during acute GVHD. Blood 2015; 125: 3183-92.

  36. Zhang J, Ramadan AM, Griesenauer B. ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graftversus- host disease. Sci Transl Med 2015; 7(308): 308-60.

  37. Tamargo Santos B, Bungau S, Fleitas Perez C, Marquez Napoles Y, Infante Bourzac JF, Oliva Hernandez R, et al. Immuno-toicological Evaluation of the Adjuvant Formulations for Experimental Anti-meningococcalVaccines without Aluminium Hydroxide. Rev Chimie (Bucharest). [Internet]. 2019 [Citado 24/06/2029];70(4):1251–7. Disponible en: http://www.revistadechimie.ro

  38. Henden AS, Hill GR. Cytokines in graft-versushost disease. J Immunol. 2015;194:4604–12.




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