Hyperthermia on skin immune system and its application in the treatment of human papillomavirus-infected skin diseases

Abstract

Hyperthermia is a condition characterized by increased body temperature as a consequence of failed thermoregulation. Hyperthermia occurs when a body produces or absorbs more heat than it dissipates. Hyperthermia also elicits various effects on the physiology of living cells. For instance, fever-range temperature (39β°C to 40β°C) can modulate the activities of immune cells, including antigen-presenting cells, T cells, and natural killer cells. Heat shock temperature (41β°C to 43β°C) can increase the immunogenicity of tumor cells. Cytotoxic temperature (>43β°C) can create an antigen source to induce an anti-tumor immune response. The immunomodulatory effect of hyperthermia has promoted an interest in hyperthermia-aided immunotherapy, particularly against tumors. Hyperthermia has also been used to treat deep fungal, bacterial, and viral skin infections. We conducted a series of open or controlled trials to treat skin human papillomavirus infection by inducing local hyperthermia. More than half of the patients were significantly cured compared with those in the control trial. A series of challenging clinical cases, such as large lesions in pregnant patients or patients with diabetes mellitus, were also successfully and safely managed using the proposed method. However, further studies should be conducted to clarify the underlying mechanisms and promote the clinical applications of hyperthermia.

Keywords

hyperthermia / HPV / immune response / virus / tumor

References

[1] Gao XH, Chen HD. Hyperthermia: recognition, prevention and treatment. New York: Nova publishers, 2012

[2] Horowitz M. Genomics and proteomics of heat acclimation. Front Biosci2010; 2(1): 1068-1080

[3] Patz JA, Campbell-Lendrum D, Holloway T, Foley JA. Impact of regional climate change on human health. Nature2005; 438(7066): 310-317

[4] Rowlands DJ, Frame DJ, Ackerley D, Aina T, Booth BBB, Christensen C, Collins M, Faull N, Forest CE, Grandey BS, Gryspeerdt E, Highwood EJ, Ingram WJ, Knight S, Lopez A, Massey N, McNamara F, Meinshausen N, Piani C, Rosier SM, Sanderson BM, Smith LA, Stone DA, Thurston M, Yamazaki K, Hiro Yamazaki Y, Allen MR. Broad range of 2050 warming from an observationally constrained large climate model ensemble. Nat Geosci2012; 5(4): 256-260

[5] Bouchama A, Knochel JP. Heat stroke. N Engl J Med2002; 346(25): 1978-1988

[6] Zhang HG, Mehta K, Cohen P, Guha C. Hyperthermia on immune regulation: a temperature’s story. Cancer Lett2008; 271(2): 191-204

[7] Hildebrandt B, Wust P, Ahlers O, Dieing A, Sreenivasa G, Kerner T, Felix R, Riess H. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol2002; 43(1): 33-56

[8] Kourtis N, Nikoletopoulou V, Tavernarakis N. Small heat-shock proteins protect from heat-stroke-associated neurodegeneration. Nature 2012; 490(7419): 213-218

[9] Kus-Liśkiewicz M, Polańska J, Korfanty J, Olbryt M, Vydra N, Toma A, Widłak W. Impact of heat shock transcription factor 1 on global gene expression profiles in cells which induce either cytoprotective or pro-apoptotic response following hyperthermia. BMC Genomics2013; 14(1): 456

[10] Sugimoto N, Shido O, Matsuzaki K, Ohno-Shosaku T, Hitomi Y, Tanaka M, Sawaki T, Fujita Y, Kawanami T, Masaki Y, Okazaki T, Nakamura H, Koizumi S, Yachie A, Umehara H. Cellular heat acclimation regulates cell growth, cell morphology, mitogen-activated protein kinase activation, and expression of aquaporins in mouse fibroblast cells. Cell Physiol Biochem2012; 30(2): 450-457

[11] Binder RJ, Vatner R, Srivastava P. The heat-shock protein receptors: some answers and more questions. Tissue Antigens2004; 64(4): 442-451

[12] Chen W, Syldath U, Bellmann K, Burkart V, Kolb H. Human 60-kDa heat-shock protein: a danger signal to the innate immune system. J Immunol1999; 162(6): 3212-3219

[13] Panjwani NN, Popova L, Srivastava PK. Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. J Immunol2002; 168(6): 2997-3003

[14] Lehner T, Bergmeier LA, Wang Y, Tao L, Sing M, Spallek R, van der Zee R. Heat shock proteins generate beta-chemokines which function as innate adjuvants enhancing adaptive immunity. Eur J Immunol2000; 30(2): 594-603

[15] Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturationsignal to dendritic cells and activate the NF-kappa B pathway. Int Immunol2002; 12(11): 1539-1546

[16] Singh-Jasuja H, Scherer HU, Hilf N, Arnold-Schild D, Rammensee HG, Toes RE, Schild H. The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor. Eur J Immunol2000; 30(8): 2211-2215

[17] Binder RJ, Anderson KM, Basu S, Srivastava PK. Cutting edge: heat shock protein gp96 induces maturation and migration of CD11c⁺ cells in vivo. J Immunol2000; 165(11): 6029-6035

[18] Wells AD, Malkovsky M. Heat shock proteins, tumor immunogenicity and antigen presentation: an integrated view. Immunol Today 2000; 21(3): 129-132PMID:10689300

[19] Jones EL, Samulski TV, Vujaskovic Z, Prosnitz LR, Dewhirst MW. In: Halperin EC, Perez CA, Brady LW. Principles and Practice of Radiation Oncology. Philadelphia: Lippincott Williams & Wilkins, 2008: 637-668

[20] Sneed PK, Hsu IC. Hyperthermia. In: Ko AH, Dollinger M, Rosenbaum EH. Everyone’s Guide to Cancer Therapy: How Cancer is Diagnosed, Treated, and Managed Day to Day. Kansas: Andrews McMeel Publishing, 2008: 98-100

[21] Bicher JI, Al-Bussam N, Wolfstein RS. Thermoradiotherapy with curative intent—breast, head, neck and prostate tumors. Dtsch Z Onkol2006; 38(3): 116-122

[22] Bos JD. Skin Immune System: Cutaneous Immunology and Clinical Immunodermatology. 3rd ed. Florida: CRC Press, 2004

[23] Li X, Gao XH, Jin L, Wang Y, Hong Y, McHepange UO, Wang X, Jiang Y, Wei H, Chen HD. Local hyperthermia could induce migrational maturation of Langerhans cells in condyloma acuminatum. J Dermatol Sci2009; 54(2): 121-123

[24] Wang X, Gao XH, Li X, Hong Y, Qi R, Chen HD, Zhang L, Wei H. Local hyperthermia induces apoptosis of keratinocytes in both normal skin and condyloma acuminata via different pathways. Apoptosis2009; 14(5): 721-728

[25] Zhu LL, Gao XH, Qi R, Hong Y, Li X, Wang X, McHepange UO, Zhang L, Wei H, Chen HD. Local hyperthermia could induce endogenous interferons gene expression via JAK-STATs signaling pathway in condyloma acuminate. Antiviral Res2010; 88(2): 187-192

[26] Huo W, Li GH, Qi RQ, Zhang L, Yan XX, Chen HD, Gao XH. Clinical and immunologic results of local hyperthermia at 44 °C for extensive genital warts in patients with diabetes mellitus. Int J Hyperthermia2013; 29(1): 17-20

[27] Zhang L, Wang YR, Hong YX, Xu YQ, Zhang L, Li XD, Xiao T, Lu DQ, Chen HD, Gao XH. Temporal effect of local hyperthermia on murine contact hypersensitivity. Chin Med J (Engl)2013; 126(8): 1555-1559

[28] zur Hausen H. Papillomaviruses—to vaccination and beyond. Biochemistry (Mosc)2008; 73(5): 498-503

[29] Huo W, Gao XH, Sun XP, Qi RQ, Hong Y, Mchepange UO, Li XD, Xiao BH, Lin JP, Jiang Y, Zhang L, Li YH, Xiao T, Chen JZ, Chen HD. Local hyperthermia at 44 °C for the treatment of plantar warts: a randomized, patient-blinded, placebo-controlled trial. J Infect Dis2010; 201(8): 1169-1172

[30] Li XD, Zhang C, Hong YX, Zhang DS, Wei HC, Chen HD, Gao XH. Local hyperthermia treatment of extensive viral warts in Darier disease: a case report and literature review. Int J Hyperthermia2012; 28(5): 451-455

[31] Ma Y, Huo W, Hong YX, Chen HD, Gao XH. Successful clearance of facial warts with local hyperthermia. Dermatol Ther2012; 25(4): 386-388

[32] Huo W, Di ZH, Xiao BH, Qi RQ, Weiland M, Gao XH. Clearance of genital warts in pregnant women. Dermatol Ther2013 (Epub ahead of print).

Acknowledgements

This study was supported by the Innovative Research Teams of Liaoning Department of Education (Grant No. LT2011012) and Public Welfare Research Fund for Healthcare (No.201202013).

Compliance with ethics guidelines

Xinghua Gao and Hongduo Chen declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg