Exogenous activated NK cells enhance trafficking of endogenous NK cells to endometriotic lesions

BMC Immunology

Per H. Basse²  Rui Alberto Ferriani¹  Mary Lourdes Montenegro¹ 

[1] Department of Gynecology and Obstetrics of Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirao Preto, SP, Brazil;Department of Immunology of University of Pittsburgh, Pittsburgh, PA, USA

关键词: Treatment;    A-NK cells;    Activated NK cells;    NK cells;    Endometriosis;   

Others  :  1224885
DOI  :  10.1186/s12865-015-0105-0

 received in 2015-01-20, accepted in 2015-06-26,  发布年份 2015

【 摘 要 】

Background

Endometriosis is defined as the presence of endometrial glands and stroma at ectopic locations. Although the prevalence of endometriosis is as high as 35 %–50 %, its pathogenesis remains controversial. An increasing number of studies suggest that changes in immune reactivity may be primarily involved in the development of endometriosis development. In this sense, it has been strongly suggested that a fundamental part of immunologic system, the natural killer cells (NK cells), are an important part of this process. NK cells, a component of the innate immune system, have been extensively studied for their ability to defend the organism against infections and malignancy. Recent studies have shown that IL-2-activated NK (A-NK) cells are able to attack and destroy tumors in lungs and livers of mice, demonstrating the therapeutic potential of these cells. Similarly to metastatic tumor cells, endometrial cells are able to adhere, infiltrate and proliferate at ectopic locations. Therefore, in this study, we evaluated the ability of adoptively transferred and endogenous NK cells to infiltrate endometriosis lesions.

Methods

As NK cells donors were used C57BL/6 B6. PL- Thy 1.1 female mice. As uterine horns donors were used C57/BL6+GFP female mice and as endometriosis recipients C57BL/6 Thy1.2 female mice. Endometriosis induction was made by injection of endometrial tissue fragments. After 4 weeks, necessary for endometriosis lesions establishment the animals were divided in 3 experimental groups with 10 animals each. Group 1 received i.v doses of 5x106 A-NK in 200μl RPMI; Group 2 received i.p dose of 5x106 A-NK in 200μl RPMI and Group 3 received i.p dose of IL2 (0.5 mL RPMI containing 5.000U of IL2).

Results

Our data show that exogenous A-NK cells injected via ip combined with endogenous A-NK cells seems to be the most efficient way for activated NK cells track and infiltrate endometriosis.

Conclusion

For the first time, it was shown that both endogenous as exogenous A-NK cells are able to track, migrate and infiltrate endometriosis lesion. This seems to be a promising result, and if confirmed the efficiency of A-NK cells in killing endometriosis lesions, maybe in the future we could use this approach as an alternative treatment for women with endometriosis.

【 授权许可】

   
2015 Montenegro et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 6.

Fig. 7.

【 参考文献 】

• [1]Giudice LC, Kao LC. Endometriosis. Lancet. 2004; 364(9447):1789-99.
• [2]Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D’Hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril. 2009; 92(1):68-74.
• [3]Braun DP, Ding J, Shen J, Rana N, Fernandez BB, Dmowski WP. Relationship between apoptosis and the number of macrophages in eutopic endometrium from women with and without endometriosis. Fertil Steril. 2002; 78(4):830-5.
• [4]Chung HW, Lee JY, Moon HS, Hur SE, Park MH, Wen Y, Polan ML. Matrix metalloproteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium. Fertil Steril. 2002; 78(4):787-95.
• [5]Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril. 2001; 75(1):1-10.
• [6]Berkkanoglu M, Arici A. Immunology and endometriosis. Am J Reprod Immunol. 2003; 50(1):48-59.
• [7]Manolova NDZ, Stamenova M. Immunobyology of Endometriosis. Acta Мedica Bulgarica. 2011; 38(01):38-50.
• [8]Basse PH, Whiteside TL, Herberman RB. Cancer immunotherapy with interleukin-2-activated natural killer cells. Mol Biotechnol. 2002; 21(2):161-70.
• [9]Yang Q, Goding SR, Hokland ME, Basse PH. Antitumor activity of NK cells. Immunol Res. 2006; 36(1–3):13-25.
• [10]Schwarz RE, Vujanovic NL, Hiserodt JC. Enhanced antimetastatic activity of lymphokine-activated killer cells purified and expanded by their adherence to plastic. Cancer Res. 1989; 49(6):1441-6.
• [11]Yang Q, Hokland ME, Bryant JL, Zhang Y, Nannmark U, Watkins SC, Goldfarb RH, Herberman RB, Basse PH. Tumor-localization by adoptively transferred, interleukin-2-activated NK cells leads to destruction of well-established lung metastases. Int J Cancer. 2003; 105(4):512-9.
• [12]Velasco I, Quereda F, Bermejo R, Campos A, Acien P. Intraperitoneal recombinant interleukin-2 activates leukocytes in rat endometriosis. J Reprod Immunol. 2007; 74(1–2):124-32.
• [13]Wieser F, Wu J, Shen Z, Taylor RN, Sidell N. Retinoic acid suppresses growth of lesions, inhibits peritoneal cytokine secretion, and promotes macrophage differentiation in an immunocompetent mouse model of endometriosis. Fertil Steril. 2012; 97(6):1430-7.
• [14]Goding S, Yang Q, Mi Z, Robbins PD, Basse PH. Targeting of products of genes to tumor sites using adoptively transferred A-NK and T-LAK cells. Cancer Gene Ther. 2007; 14(5):441-50.
• [15]Bacci M, Capobianco A, Monno A, Cottone L, Di Puppo F, Camisa B, Mariani M, Brignole C, Ponzoni M, Ferrari S et al.. Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease. Am J Pathol. 2009; 175(2):547-56.
• [16]Burns KA, Rodriguez KF, Hewitt SC, Janardhan KS, Young SL, Korach KS. Role of estrogen receptor signaling required for endometriosis-like lesion establishment in a mouse model. Endocrinology. 2012; 153(8):3960-71.
• [17]Mariani M, Vigano P, Gentilini D, Camisa B, Caporizzo E, Di Lucia P, Monno A, Candiani M, Somigliana E, Panina-Bordignon P. The selective vitamin D receptor agonist, elocalcitol, reduces endometriosis development in a mouse model by inhibiting peritoneal inflammation. Hum Reprod. 2012; 27(7):2010-9.
• [18]Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997, 67(5):817–21.