Ameliorative Effects of Monoclonal Antibodies (CD3 and PCNA) on the Immunomodulation of Mesenchymal Stem Cells in Male Mice

doi.org/10.26538/tjnpr/v5i9.16

Authors

  • Nabil A Soliman Department of Zoology, Faculty of Science, Zagazig University, Egypt
  • Heba M Saad El-Dien Tissue Culture and Molecular Biology Center, Faculty of Medicine, Assuit University, Egypt
  • Aya Hussin Department of Zoology, Faculty of Science, Zagazig University, Egypt

Keywords:

Cluster of differentiation, Cyclophosphamide, Mesenchymal stem cell, Proliferating cell nuclear antigen, T-cells

Abstract

Mesenchymal stem cell (MSC) is being used in regenerative medicine and also for the treatment of autoimmune diseases and graft-versus-host disease. Cyclophosphamide (CTX) is a chemotherapeutic agent used for the treatment of cancer as well as several immunological diseases. The present study was designed to evaluate the therapeutic role of bone marrow-derived mesenchymal stem cells (BM-MSCs) in ameliorating the adverse effect of cyclophosphamide-induced immunohistochemical toxicity in adult male albino mice. Forty male albino mice of matched age were used for this study. They were divided into four equal groups. Group I served as the control; Group II was treated with cyclophosphamide (CTX); Group III was administered with cyclophosphamide concomitantly with MSCs; while the fourth group was used to isolate bone marrow. Blood leukocyte, splenocyte numbers, blood cell type levels, and splenocyte were determined after one month of initiation of the experiment. Two markers; the cluster of differentiation 3 (CD3) and proliferating cell nuclear antigen (PCNA) were used for immunohistochemical analysis. The results showed that CTX induced a reduction in overall proliferating cells in splenic parenchyma with clear CD3 positive cells in the periarterial sheath. MSCs induced reduction in T-cell number sparing other cells as indicated from intense cell proliferation in the splenic white and red pulp in this group of animals. The study demonstrated that MSCs induced reduction of T-cell number associated with a proliferation of other immune cells of the spleen. 

References

FrIedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic transplants of bone marrow. Transplant. 1968; 6 (2):230-247.

Umberto G and Giordano A. The gap between the physiological and therapeutic roles of mesenchymal stem cells. Med Res Rev. 2014; 34(5):1100-1126.

Chen L, Trudged EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS ONE. 2008; 3(4): e1886.

Liu HH, Chen FP, Liu RK, Lin C, Chang KT. Ginsenoside Rg1 improves bone marrow haematopoietic activity via extramedullary haematopoiesis of the spleen. J Cell Mol Med. 2015; 19(11):2575-2586.

Roux C, Saviane G, Pini J, Belaïd N, Dhib G, Voha C, Ibáñez L, Boutin A, Nathalie M, Mazure D, Wakkach A,Wakkach CB, Rouleau, M. Immunosuppressive mesenchymal stromal cells derived from human-induced pluripotent stem cells induce human regulatory T cells in

vitro and in vivo. Front Immunol. 2018; 8:1991-1992.

Melief SM, Schrama E, Brugman MH, Tiemessen MM, Hoogduijn M J, Fibbe WE, Roelofs H. Multipotentstromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward antiinflammatory macrophages. Stem Cells. 2013; 31(9):1980-1991.

Si YL, Xiao LJ, DongHan BFW. MSCs: biological characteristics, clinical applications, and their outstanding concerns. Aging Res Rev. 2011; 10(1):93-103.

Abumaree M, Al Jumah M, Pace RA, Kalionis B. Immunosuppressive properties of mesenchymal stem cells.Stem Cell Rev Rep. 2012; 8(2):375-392.

Taechangam N,Iyer SS, Walker NJ, Arzi B, Borjesson DL. Mechanisms utilized by feline adipose-derived mesenchymal stem cells to inhibit T lymphocyte proliferation. Stem Cell Res Ther. 2019; 10(1):1-12.

Benvenuto F, Ferrari S, Gerdoni E, Gualandi F, Frassoni F, Pistoia V, Mancardi G, Uccelli A. Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem Cells. 2007; 25(7):1753-1760.

Espagnollem N, Balguerie A, Arnaud E, Sensebé L, VarinA. CD54-mediated interaction with pro-inflammatory macrophages increases the immunosuppressive function of human mesenchymal stromal cells. Stem Cell Rep. 2017; 8(4): 961-976.

Glennie S, Soeiro I, Dyson PJ, Lam EWF, Crossmark FD. Bone marrow mesenchymal stem cells induce division arrest energy of activated T cells. Blood. 2005; 105(7):2821-2827.

Sabine G and Stamenkovic I. Mesenchymal stromal cells in cancer: a review of their immunomodulatory functions and dual effects on tumor progression. J Pathol. 2020; 250(5):555-572.

Kazuhisa N and Seki R. Mechanisms of immunosuppression by mesenchymal stromal cells: a review with a focus on molecules. Biomed Res Clin Prac. 2016; 1(3): 82-96.

Liu K, Wang GB, Cheng B, Qiu DB. Clinical comparison of GC regimen (gemcitabine and cisplatin) versus FEC regimen (fluorouracil, epirubicin, and cyclophosphamide) as neoadjuvant chemotherapy for breast cancer. Chin J Cancer. 2007; 26(4): 427-430.

Yeh CH, Chien LC, Chiang YC, Lin SW, Huang CK, Ren D. Reduction in nausea and vomiting in children undergoing cancer chemotherapy by either appropriate or sham auricular acupuncture points with standard care. J Altern Compl Med. 2012; 18(4):334-340

Botnick LE, Hannon EC, Vigneulle R, Hellman S. Differential effects of cytotoxic agents on hematopoietic progenitors. Cancer Res. 1981; 41(6):7338-7342.

Ding ZC, Lu X, Yu M, Lemos H., Huang L, Chandler P, Liu K, Walters M, Krasinski A, Mack M, Blazar BR, Mellor AL, Munn DH, Zhou G. Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1–PD-L1 axis. Cancer Res. 2014; 74(13):3441-3453.

Petrucci MT, Avvisati G, La Verde G, De Fabritiis P, Ribersani M, Palumbo G, De Felice L, Rusignuolo A. Simone F, Meloni G, Mandelli F. intermediate-dose cyclophosphamide and granulocyte colony-stimulating factor is a valid alternative to high-dose cyclophosphamide

for mobilizing peripheral blood CD34+ cells in patients with multiple myeloma. Acta Haematol. 2003; 109(4):184-188.

Atallah E, Abrams J, Uberti J. Long term follow up of allogeneic stem cell transplantation in patients with myelodysplastic syndromes using busulfan, cytosine arabinoside, and cyclophosphamide. Am J Hematol. 2010; 85(8): 579-583.

De Jonge ME, Huitema AD, Rodenhuis S, Beijnen JH. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet. 2005; 44(11):1135-1164.

Wang E, Ouellet N, Simard M, Fillion I, Bergeron Y, Beauchamp D, Bergeron MG. Pulmonary and systemic host response to Streptococcus pneumoniae and Klebsiella pneumoniae bacteremia in normal and immunosuppressed mice. Infect Immun. 2001; 69(9):5294-5304.

Kim YH, Orc ID, Cho KA, Lee HJ, Park MI, Shin SJ, Park JW, So-Youn Woo 1, Ryu KH. Conditioned Medium from Human Tonsil-Derived Mesenchymal Stem Cells Enhances Bone Marrow Engraftment via Endothelial Cell Restoration by Pleiotrophin. Cells. 2020; 9(1):221.

Karaoz E, Aksoy A, Ayhan S, Sarıboyacı AE, Kaymaz F, Kasap M. Characterization of mesenchymal stem cells from rat bone marrow: ultrastructural properties, differentiation potential, and immunophenotypic markers. Histochem. Cell Biol. 2009; 132(5):533-546

Ponnaiyan D, Bhat KM, Bhat GS. Comparison of ImmunoPhenotypes of Stem Cells from Human Dental Pulp and Periodontal Ligament. Int. J Immunopathol Pharmacol. 2012; 25(1):127-134.

Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-BorokIV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues: cloning in vitro and retransplantation in vivo. Transplant. 1974; 17(4): 331-340.

Horwitz EM, Blanc KL, Dominici M. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytother. 2005;7(5):393-395.

Lorenzi B, Pessina F, Lorenzoni P, Urbani S, Vernillo R, Sgaragli G, Gerli R, Mazzanti B, Bosi A, Saccardi R, Lorenzi M. Treatment of experimental injury of anal sphincters with primary surgical repair and injection of bone marrow-derived mesenchymal stem cells. Dis Colon

Rectum. 2008; 51(4):411-420.

Peng L, Jia Z, Yin X, Zhang X, Liu Y, Chen P, Ma K, Zhou C. Comparative analysis of mesenchymal stem cells from bone marrow cartilage and adipose tissue. Stem Cells Dev. 2008; 17(4):761-773.

Wakitani S, Saito T, Caplan Al. Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve. 1995; 18(12):1417-1426.

Hoffmann A and Gross G. Tendon, ligament. engineering in the adult organism: mesenchymal stem cells and genetherapeutic pproaches. Int Orthop. 2007; 31(6):791-797.

De Macedo Braga LM, Lacchini S, Schaan BD. In situ delivery of bone marrow cells and mesenchymal stem cells improves cardiovascular function in hypertensive rats submitted to myocardial infarction. J Biomed Sci. 2008; 15 (3):365-374.

Nauta AJ and Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007; 110(10): 3499-3506.

Keating A. How do mesenchymal stromal cells suppress T cells? Cell stem cell. 2008; 2(2):106-108.

Castro-Manrreza ME and Montesinos JJ. Immunoregulation by mesenchymal stem cells: Biological aspects and clinical applications. J Immunol. 2015; 2015: |Article ID 394917 |.

Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y. Mesenchymal Stem Cell-Mediated Immunosuppression Occurs via Concerted Action of Chemokines and Nitric Oxide. Cell Stem Cell. 2008; 2(2):141-150.

Horwitz ME, Andreef M, Frassoni F. Mesenchymal Stromal Cells. Curr Opin Hematol. 2006; 13(6):419-425.

Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigenspecific T cells to their cognate peptide. Blood. 2003; 101(9):3722-3729.

Nicola MD, Carlo-Stella CC, Magni M, Milanesi M,Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002; 99(10): 3838–3843.

Rasmusson I, Ringden O, Sundberg B, Blanc LK. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Cell Res. 2005; 305(1):33-41.

Chiossone L, Conte R, Spaggiari GM, Serra M, Romei C, Bellora F, Becchetti F, Andaloro A, Moretta L, Bottino C. Mesenchymal Stromal Cells Induce Peculiar Alternatively Activated Macrophages Capable of Dampening Both Innate and Adaptive Immune Responses. Stem Cells.

; 34(7):1909-1921.

Zhou Y, Yamamoto Y, Xiao Z, Ochiya T. The immunomodulatory functions of mesenchymal stromal/stem cells mediated via paracrine activity. J Clin Med. 2019; 8(7):1025.

Sato K, Azaki K, Oh I, Meguro A, Hatanaka K, Nagai T, Muroi K., Ozawa K. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood. 2007; 109(1):228-234.

Chiossone L, Conte R, Spaggiari GM, Serra M, Romei C, Bellora F, Becchetti F, Andaloro A, Moretta L, Bottino, C. Mesenchymal Stromal Cells Induce Peculiar Alternatively Activated Macrophages Capable of Dampening Both Innate and Adaptive Immune Responses. Stem Cells. 2016; 34(7):1909-1921.

Zhao Q, Ren H, Han Z. Mesenchymal stem cells: Immunomodulatory capability and clinical potential in immune diseases. J Cell Immunother. 2016; 2(1): 3-20.

Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol. 2003; 57(1):11-20.

Klyushnenkova E, Mosca JD, Zernetkina V, Manas K, Majumdar MK, Beggs KJ, Simonetti Dw , Deans RJ, McIntosh KR. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci. 2005; 12(1):47-57.

Li N and Hua J. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci. 2017; 74(13): 2345-2360.

Galipeau J and Sensébé L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Stem Cell. 2018; 22(6): 824-833.

Nishizawa K and Seki R. Mechanisms of immunosuppression by mesenchymal stromal cells: a review with a focus on molecules. Biomed Res Clin Prac.2016; 1:82-96.

Kim JH, Lee YT, Hong JM, Hwang YI. Suppression of in vitro murine T cell proliferation by human adipose tissuederived mesenchymal stem cells is dependent mainly on cyclooxygenase-2 expression. Anat Cell Biol. 2013; 46(4):262-271.

Chen K, Wang D, Du WT, Han ZB, Ren H, Chi Y, Yang SG, Zhu D, Bayard F, Han ZC. Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism. Clin Immunol. 2010; 135(3):448- 458.

Ling W, Zhang J, Yuan Z, Ren G, Zhang L, Chen X, Arnold B, Rabson AB, Roberts AI, Wang Y, Shi Y. Mesenchymal stem cells use IDO to regulate immunity in the tumor microenvironment. Cancer Res. 2014; 74(5):1576- 1587.

Yen BL, Yen ML, Hsu PJ, Liu KJ, Wang CJ, Bai CH, Sytwu HK. Multipotent human mesenchymal stromal cells mediate expansion of myeloid-derived suppressor cells via hepatocyte growth factor/c-Met and STAT3. Stem Cell Rep. 2013; 1(2): 139-151.

Xu CL, Yu PF, Han XY, Du LM, Gan JH, Wang Y, Shi Y. TGF-beta promotes immune responses in the presence of mesenchymal stem cells. J Immunol. 2014; 192(1):103-109.

Rafei M, Campeau PM, Mahecha AA, Buchanan M, Williams P, Birman E, Yuan S, Young YK, Boivin MN, Forner K, Basik M, Galipeau J. Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. J Immunol. 2009; 182(10):5994-6002.

Schurch CM, Riether C, Ochsenbein AF. Cytotoxic CD8+ T-cells stimulate hematopoietic progenitors by promoting cytokine release from bone marrow mesenchymal stromal cells. Cell Stem Cell. 2014; 14(4):460e72.

Downloads

Published

2021-09-01

How to Cite

A Soliman, N., M Saad El-Dien, H., & Hussin, A. (2021). Ameliorative Effects of Monoclonal Antibodies (CD3 and PCNA) on the Immunomodulation of Mesenchymal Stem Cells in Male Mice: doi.org/10.26538/tjnpr/v5i9.16. Tropical Journal of Natural Product Research (TJNPR), 5(9), 1626–1633. Retrieved from https://tjnpr.org/index.php/home/article/view/428