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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2014, Vol. 8 Issue (1) : 1-5     DOI: 10.1007/s11684-014-0309-3
Hyperthermia on skin immune system and its application in the treatment of human papillomavirus-infected skin diseases
Xinghua Gao(), Hongduo Chen
Department of Dermatology, the First Hospital of China Medical University, Shenyang 110001, China
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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     
Corresponding Authors: Gao Xinghua,   
Issue Date: 26 April 2014
URL:     OR
HSPHSP receptor(s)
gp96CD91, TLR-2, TLR-4, SR-A
HSP60CD14, TLR-4, TLR-2
HSP70CD14, CD40, CD91, Lox-1,TLR-2, TLR-4
CalreticulinCD91, SR-A
Tab.1  Characterized HSPs and associated receptors (adopted and revised from Ref.β[-])
Fever-range (39β°C to 40β°C) and heat shock (41β°C to 43β°C) temperatureIncreases antigen uptake and phagocytosis by DCs and macrophagesStimulates antigen processing by increasing the expression of immunoproteasome, lmp2, and lmp7Augments cross-presentation in DCs and primes naive CD8+ T cells to form CTLsInduces DC activation and maturationEnhances the migration of DCs to draining lymph nodesIncreases the expression of TLR4Upregulates the expression of MHC class II, CD80, CD86, and CD40 in DCsPromotes lymphocyte trafficking to lymphoid and tumor tissueRegulates lymphocyte survival and persistence in peripheral tissue by inducing c-FLIP degradationEnhances the effector T cell function: increased expression of CD95L in CTLs and augment NK cell migration and lysisIncreases class I MHC expression on tumor cell surfaceUpregulates the expression of tumor antigensInduces expression of HSPs that provide “danger signal” for DC activationEnhances the susceptibility of tumor cells to CTL-mediated lysis
Cytotoxic temperature (>43β°C)Creates an antigen source to induce an anti-tumor immune response
Tab.2  Immunomodulating effects of hyperthermia (adopted and revised from Ref. [])
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 Biosci 2010; 2(1): 1068-1080
doi: 10.2741/S118 pmid:20515841
3 Patz JA, Campbell-Lendrum D, Holloway T, Foley JA. Impact of regional climate change on human health. Nature 2005; 438(7066): 310-317
doi: 10.1038/nature04188 pmid:16292302
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 Geosci 2012; 5(4): 256-260
doi: 10.1038/ngeo1430
5 Bouchama A, Knochel JP. Heat stroke. N Engl J Med 2002; 346(25): 1978-1988
doi: 10.1056/NEJMra011089 pmid:12075060
6 Zhang HG, Mehta K, Cohen P, Guha C. Hyperthermia on immune regulation: a temperature’s story. Cancer Lett 2008; 271(2): 191-204
doi: 10.1016/j.canlet.2008.05.026 pmid:18597930
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 Hematol 2002; 43(1): 33-56
doi: 10.1016/S1040-8428(01)00179-2 pmid:12098606
8 Kourtis N, Nikoletopoulou V, Tavernarakis N. Small heat-shock proteins protect from heat-stroke-associated neurodegeneration. Nature 2012; 490(7419): 213-218
doi: 10.1038/nature11417 pmid:22972192
9 Kus-Li?kiewicz M, Polańska J, Korfanty J, Olbryt M, Vydra N, Toma A, Wid?ak 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 Genomics 2013; 14(1): 456
doi: 10.1186/1471-2164-14-456 pmid:23834426
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 Biochem 2012; 30(2): 450-457
doi: 10.1159/000339038 pmid:22814242
11 Binder RJ, Vatner R, Srivastava P. The heat-shock protein receptors: some answers and more questions. Tissue Antigens 2004; 64(4): 442-451
doi: 10.1111/j.1399-0039.2004.00299.x pmid:15361121
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 Immunol 1999; 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 Immunol 2002; 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 Immunol 2000; 30(2): 594-603
doi: 10.1002/1521-4141(200002)30:2<594::AID-IMMU594>3.0.CO;2-1 pmid:10671216
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 Immunol 2002; 12(11): 1539-1546
doi: 10.1093/intimm/12.11.1539
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 Immunol 2000; 30(8): 2211-2215
doi: 10.1002/1521-4141(2000)30:8<2211::AID-IMMU2211>3.0.CO;2-0 pmid:10940912
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 Immunol 2000; 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): 129-132
doi: 10.1016/S0167-5699(99)01558-3 pmid: PMID: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 Onkol 2006; 38(3): 116-122
doi: 10.1055/s-2006-952049
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 Sci 2009; 54(2): 121-123
doi: 10.1016/j.jdermsci.2008.12.004 pmid:19155157
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. Apoptosis 2009; 14(5): 721-728
doi: 10.1007/s10495-009-0344-8 pmid:19363704
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 Res 2010; 88(2): 187-192
doi: 10.1016/j.antiviral.2010.08.012 pmid:20797409
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 Hyperthermia 2013; 29(1): 17-20
doi: 10.3109/02656736.2012.758874 pmid:23311375
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
doi: 10.1134/S0006297908050027 pmid:18605974
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 Dis 2010; 201(8): 1169-1172
doi: 10.1086/651506 pmid:20199243
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 Hyperthermia 2012; 28(5): 451-455
doi: 10.3109/02656736.2012.677929 pmid:22690793
31 Ma Y, Huo W, Hong YX, Chen HD, Gao XH. Successful clearance of facial warts with local hyperthermia. Dermatol Ther 2012; 25(4): 386-388
doi: 10.1111/j.1529-8019.2012.01470.x pmid:22950567
32 Huo W, Di ZH, Xiao BH, Qi RQ, Weiland M, Gao XH. Clearance of genital warts in pregnant women. Dermatol Ther 2013 (Epub ahead of print).
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