Immunotherapy

From Wikipedia, the free encyclopedia
Jump to: navigation, search
For the academic journal, see Immunotherapy (journal).
Immunotherapy
Intervention
MeSH D007167
OPS-301 code 8-03

Immunotherapy is the "treatment of disease by inducing, enhancing, or suppressing an immune response".[1] Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies.

Immunomodulatory regimens often have fewer side effects than existing drugs, including less potential for creating resistance in microbial disease.[2]

Cell-based immunotherapies are effective for some cancers. Immune effector cells such as lymphocytes, macrophages, dendritic cells, natural killer cells (NK Cell), cytotoxic T lymphocytes (CTL), etc., work together to defend the body against cancer by targeting abnormal antigens expressed on the surface of tumor cells.

Therapies such as granulocyte colony-stimulating factor (G-CSF), interferons, imiquimod and cellular membrane fractions from bacteria are licensed for medical use. Others including IL-2, IL-7, IL-12, various chemokines, synthetic cytosine phosphate-guanosine (CpG) oligodeoxynucleotides and glucans are involved in clinical and preclinical studies.

Immunomodulators[edit]

Immunomodulators are the active agents of immunotherapy. They are a diverse array of recombinant, synthetic and natural preparations.

Class Example agents
Interleukins IL-2, IL-7, IL-12
Cytokines Interferons, G-CSF, Imiquimod
Chemokines CCL3, CCL26, CXCL7
Immunomodulatory imide drugs (IMiDs) thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast)
Other cytosine phosphate-guanosine, oligodeoxynucleotides, glucans

Activation immunotherapies[edit]

Cancer[edit]

Main article: Cancer immunotherapy

Cancer immunotherapy attempts to stimulate the immune system to destroy tumors. A variety of strategies are in use or are undergoing research and testing. Randomized controlled studies in different cancers resulting in significant increase in survival and disease free period have been reported[3][4][5][6] and its efficacy is enhanced by 20–30% when cell-based immunotherapy is combined with conventional treatment methods.[citation needed]

The extraction of G-CSF lymphocytes from the blood and expanding in vitro against a tumour antigen before reinjecting the cells[7] with appropriate stimulatory cytokines. The cells then destroy the tumor cells that express the antigen.[citation needed]

BCG immunotherapy[8] for early stage (non-invasive) bladder cancer instills attenuated live bacteria into the bladder and is effective in preventing recurrence in up to two thirds of cases.

Topical immunotherapy utilizes an immune enhancement cream (imiquimod) which produces interferon, causing the recipient's killer T cells to destroy warts,[9] actinic keratoses, basal cell cancer, vaginal intraepithelial neoplasia,[10] squamous cell cancer,[8][11] cutaneous lymphoma,[12] and superficial malignant melanoma.[13]

Injection immunotherapy ("intralesional" or "intratumoral") uses mumps, candida, the HPV vaccine[14][15] or trichophytin antigen injections to treat warts (HPV induced tumors).

Adoptive cell transfer has been tested on lung and other cancers.[16]

Dendritic cell-based pump-priming[edit]

Dendritic cells can be stimulated to activate a cytotoxic response towards an antigen. Dendritic cells, a type of antigen presenting cell, are harvested from the person needing the immunotherapy. These cells are then either pulsed with an antigen or tumor lysate[17] or transfected with a viral vector, causing them to display the antigen. Upon transfusion into the person, these activated cells present the antigen to the effector lymphocytes (CD4+ helper T cells, cytotoxic CD8+ T cells and B cells). This initiates a cytotoxic response against tumor cells expressing the antigen (against which the adaptive response has now been primed).[18] The cancer vaccine Sipuleucel-T is one example of this approach.[19]

T-cell adoptive transfer[edit]

Adoptive cell transfer in vitro cultivates autologous, extracted T cells for later transfusion.[20] The T cells may already target tumor cells. Alternatively, they may be genetically engineered to do so. These T cells, referred to as tumor-infiltrating lymphocytes (TIL), are multiplied using high concentrations of Interleukin-2, anti-CD3 and allo-reactive feeder cells. These T cells are then transferred back into the person along with administration of IL-2 to further boost their anti-cancer activity.

Before reinfusion, lymphodepletion of the recipient is required to eliminate regulatory T cells as well as unmodified, endogenous lymphocytes that compete with the transferred cells for homeostatic cytokines.[20][21][22][23] Lymphodepletion can be achieved by total body irradiation.[24] Transferred cells multiplied in vivo and persisted in peripheral blood in many people, sometimes representing levels of 75% of all CD8+ T cells at 6–12 months after infusion.[25] As of 2012, clinical trials for metastatic melanoma were ongoing at multiple sites.[26]

Immune enhancement therapy[edit]

Autologous immune enhancement therapy use a person's own peripheral blood-derived natural killer cells, cytotoxic T lymphocytes and other relevant immune cells are expanded in vitro and then reinfused.[27] The therapy has been tested against Hepatitis C,[28][29][30] Chronic fatigue syndrome[31][32] and HHV6 infection.[33]

Genetically engineered T cells[edit]

Genetically engineered T cells are created by harvesting T cells and then infecting the T cells with a retrovirus that contains a copy of a T cell receptor (TCR) gene that is specialised to recognise tumour antigens. The virus integrates the receptor into the T cells' genome. The cells are expanded non-specifically and/or stimulated. The cells are then reinfused and produce an immune response against the tumour cells.[34] The technique has been tested on refractory stage IV metastatic melanomas[20] and advanced skin cancer[35][36][37]

Immune recovery[edit]

Another potential use of immunotherapy is to restore the immune system of people with immune deficiencies. Cytokines, Interleukin-7 and Interleukin-2 have been tested in clinical trials.

Vaccination[edit]

Antimicrobial immunotherapy, which includes vaccination, involves activating the immune system to respond to an infectious agent.

Suppression immunotherapies[edit]

Immune suppression dampens an abnormal immune response in autoimmune diseases or reduces a normal immune response to prevent rejection of transplanted organs or cells.

Immunosuppressive drugs[edit]

Immunosuppressive drugs help manage organ transplantation and autoimmune disease. Immune responses depend on lymphocyte proliferation. Cytostatic drugs are immunosuppressive. Glucocorticoids are somewhat more specific inhibitors of lymphocyte activation, whereas inhibitors of immunophilins more specifically target T lymphocyte activation. Immunosuppressive antibodies target steps in the immune response. Other drugs modulate immune responses.

Immune tolerance[edit]

Main article: Immune tolerance

The body naturally does not launch an immune system attack on its own tissues. Immune tolerance therapies seek to reset the immune system so that the body stops mistakenly attacking its own organs or cells in autoimmune disease or accepts foreign tissue in organ transplantation.[38] Creating immunity reduces or eliminates the need for lifelong immunosuppression and attendant side effects. It has been tested on transplantations, and type 1 diabetes or other autoimmune disorders.

Allergies[edit]

Immunotherapy is used to treat allergies. While allergy treatments (such as antihistamines or corticosteroids) treat allergic symptoms, immunotherapy can reduce sensitivity to allergens, lessening its severity.

Immunotherapy may produce long-term benefits.[39] Immunotherapy is partly effective in some people and ineffective in others, but it offers allergy sufferers a chance to reduce or stop their symptoms.

The therapy is indicated for people who are extremely allergic or who cannot avoid specific allergens. Immunotherapy is generally not indicated for food or medicinal allergies. This therapy is particularly useful for people with allergic rhinitis or asthma.

The first dose contain tiny amounts of the allergen or antigen. Dosages increase over time, as the person becomes desensitized. This technique has been tested on infants to prevent peanut allergies.[40]

Helminthic therapies[edit]

Whipworm ova (Trichuris suis) and Hookworm (Necator americanus) have been tested for immunological diseases and allergies. Helminthic therapy has been investigated as a treatment for relapsing remitting multiple sclerosis[41] Crohn’s,[42][43][44] allergies and asthma.[45] The mechanism of how the helminths modulate the immune response, is unknown. Hypothesized mechanisms include re-polarisation of the Th1 / Th2 response[46] and modulation of dendritic cell function.[47][48] The helminths down regulate the pro-inflammatory Th1 cytokines, Interleukin-12 (IL-12), Interferon-Gamma (IFN-γ) and Tumour Necrosis Factor-Alpha (TNF-ά), while promoting the production of regulatory Th2 cytokines such as IL-10, IL-4, IL-5 and IL-13.[46][49]

Co-evolution with helminths has shaped some of the genes associated with Interleukin expression and immunological disorders, such Crohn's, ulcerative colitis and Celiac disease. Helminth's relationship to humans as hosts should be classified as mutualistic or symbiotic.[citation needed]

See also[edit]

References[edit]

  1. ^ "immunotherapies definition". Dictionary.com. Retrieved 2009-06-02. 
  2. ^ Masihi KN (July 2001). "Fighting infection using immunomodulatory agents". Expert Opin Biol Ther. 1 (4): 641–53. doi:10.1517/14712598.1.4.641. PMID 11727500. 
  3. ^ Fujita K, Ikarashi H, Takakuwa K, Kodama S, Tokunaga A, Takahashi T, Tanaka K (May 1995). "Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes". Clin. Cancer Res. 1 (5): 501–7. PMID 9816009. 
  4. ^ Kimura H, Yamaguchi Y (July 1997). "A phase III randomized study of interleukin-2 lymphokine-activated killer cell immunotherapy combined with chemotherapy or radiotherapy after curative or noncurative resection of primary lung carcinoma". Cancer. 80 (1): 42–9. doi:10.1002/(SICI)1097-0142(19970701)80:1<42::AID-CNCR6>3.0.CO;2-H. PMID 9210707. 
  5. ^ Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T (September 2000). "Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial". Lancet. 356 (9232): 802–7. doi:10.1016/S0140-6736(00)02654-4. PMID 11022927. 
  6. ^ Kono K, Takahashi A, Ichihara F, Amemiya H, Iizuka H, Fujii H, Sekikawa T, Matsumoto Y (June 2002). "Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer: a randomized trial". Clin. Cancer Res. 8 (6): 1767–71. PMID 12060615. 
  7. ^ Li K, Li CK, Chuen CK, Tsang KS, Fok TF, James AE, Lee SM, Shing MM, Chik KW, Yuen PM (February 2005). "Preclinical ex vivo expansion of G-CSF-mobilized peripheral blood stem cells: effects of serum-free media, cytokine combinations and chemotherapy". Eur. J. Haematol. 74 (2): 128–35. doi:10.1111/j.1600-0609.2004.00343.x. PMID 15654904. 
  8. ^ a b Järvinen R, Kaasinen E, Sankila A, Rintala E (August 2009). "Long-term efficacy of maintenance bacillus Calmette-Guérin versus maintenance mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up". Eur. Urol. 56 (2): 260–5. doi:10.1016/j.eururo.2009.04.009. PMID 19395154. 
  9. ^ van Seters M, van Beurden M, ten Kate FJ, Beckmann I, Ewing PC, Eijkemans MJ, Kagie MJ, Meijer CJ, Aaronson NK, Kleinjan A, Heijmans-Antonissen C, Zijlstra FJ, Burger MP, Helmerhorst TJ (April 2008). "Treatment of vulvar intraepithelial neoplasia with topical imiquimod". N. Engl. J. Med. 358 (14): 1465–73. doi:10.1056/NEJMoa072685. PMID 18385498. 
  10. ^ Buck HW, Guth KJ (October 2003). "Treatment of vaginal intraepithelial neoplasia (primarily low grade) with imiquimod 5% cream". J Low Genit Tract Dis. 7 (4): 290–3. doi:10.1097/00128360-200310000-00011. PMID 17051086. 
  11. ^ Davidson HC, Leibowitz MS, Lopez-Albaitero A, Ferris RL (September 2009). "Immunotherapy for head and neck cancer". Oral Oncol. 45 (9): 747–51. doi:10.1016/j.oraloncology.2009.02.009. PMID 19442565. 
  12. ^ Dani T, Knobler R (2009). "Extracorporeal photoimmunotherapy-photopheresis". Front. Biosci. 14 (14): 4769–77. doi:10.2741/3566. PMID 19273388. 
  13. ^ Eggermont AM, Schadendorf D (June 2009). "Melanoma and immunotherapy". Hematol. Oncol. Clin. North Am. 23 (3): 547–64, ix–x. doi:10.1016/j.hoc.2009.03.009. PMID 19464602. 
  14. ^ Chuang CM, Monie A, Wu A, Hung CF (2009). "Combination of apigenin treatment with therapeutic HPV DNA vaccination generates enhanced therapeutic anti tumor effects". J. Biomed. Sci. 16 (1): 49. doi:10.1186/1423-0127-16-49. PMC 2705346Freely accessible. PMID 19473507. 
  15. ^ Pawlita M, Gissmann L (April 2009). "[Recurrent respiratory papillomatosis: indication for HPV vaccination?]". Dtsch. Med. Wochenschr. (in German). 134 Suppl 2: S100–2. doi:10.1055/s-0029-1220219. PMID 19353471. 
  16. ^ Kang N, Zhou J, Zhang T, Wang L, Lu F, Cui Y, Cui L, He W (August 2009). "Adoptive immunotherapy of lung cancer with immobilized anti-TCRgammadelta antibody-expanded human gammadelta T-cells in peripheral blood". Cancer Biol. Ther. 8 (16): 1540–9. doi:10.4161/cbt.8.16.8950. PMID 19471115. 
  17. ^ Gao, Daiqing; Li, Changyou; Xie, Xihe; Zhao, Peng; Wei, Xiaofang; Sun, Weihong; Liu, Hsin-Chen; Alexandrou, Aris T.; Jones, Jennifer (2014-01-01). "Autologous tumor lysate-pulsed dendritic cell immunotherapy with cytokine-induced killer cells improves survival in gastric and colorectal cancer patients". PloS One. 9 (4): e93886. doi:10.1371/journal.pone.0093886. ISSN 1932-6203. PMC 3974849Freely accessible. PMID 24699863. 
  18. ^ Overes IM, Fredrix H, Kester MG, Falkenburg JH, van der Voort R, de Witte TM, Dolstra H (2009). "Efficient activation of LRH-1-specific CD8+ T-cell responses from transplanted leukemia patients by stimulation with P2X5 mRNA-electroporated dendritic cells". J. Immunother. 32 (6): 539–51. doi:10.1097/CJI.0b013e3181987c22. PMID 19483655. 
  19. ^ Di Lorenzo G, Buonerba C, Kantoff PW (September 2011). "Immunotherapy for the treatment of prostate cancer". Nature Reviews Clinical Oncology. 8 (9): 551–61. doi:10.1038/nrclinonc.2011.72. PMID 21606971. 
  20. ^ a b c Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME (April 2008). "Adoptive cell transfer: a clinical path to effective cancer immunotherapy". Nature Reviews Cancer. 8 (4): 299–308. doi:10.1038/nrc2355. PMC 2553205Freely accessible. PMID 18354418. 
  21. ^ Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, Palmer DC, Chan CC, Klebanoff CA, Overwijk WW, Rosenberg SA, Restifo NP (March 2005). "CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells". Journal of Immunology. 174 (5): 2591–601. doi:10.4049/jimmunol.174.5.2591. PMC 1403291Freely accessible. PMID 15728465. 
  22. ^ Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, Hwang LN, Yu Z, Wrzesinski C, Heimann DM, Surh CD, Rosenberg SA, Restifo NP (October 2005). "Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells". J. Exp. Med. 202 (7): 907–12. doi:10.1084/jem.20050732. PMC 1397916Freely accessible. PMID 16203864. 
  23. ^ Dummer W, Niethammer AG, Baccala R, Lawson BR, Wagner N, Reisfeld RA, Theofilopoulos AN (July 2002). "T cell homeostatic proliferation elicits effective antitumor autoimmunity". J. Clin. Invest. 110 (2): 185–92. doi:10.1172/JCI15175. PMC 151053Freely accessible. PMID 12122110. 
  24. ^ Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA (November 2008). "Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens". J. Clin. Oncol. 26 (32): 5233–9. doi:10.1200/JCO.2008.16.5449. PMC 2652090Freely accessible. PMID 18809613. 
  25. ^ Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA (October 2002). "Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes". Science. 298 (5594): 850–4. doi:10.1126/science.1076514. PMC 1764179Freely accessible. PMID 12242449. 
  26. ^ Pilon-Thomas S, Kuhn L, Ellwanger S, Janssen W, Royster E, Marzban S, Kudchadkar R, Zager J, Gibney G, Sondak VK, Weber J, Mulé JJ, Sarnaik AA (October 2012). "Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma". J. Immunother. 35 (8): 615–20. doi:10.1097/CJI.0b013e31826e8f5f. PMID 22996367. 
  27. ^ Manjunath SR, Ramanan G, Dedeepiya VD, Terunuma H, Deng X, Baskar S, Senthilkumar R, Thamaraikannan P, Srinivasan T, Preethy S, Abraham SJ (January 2012). "Autologous immune enhancement therapy in recurrent ovarian cancer with metastases: a case report". Case Rep Oncol. 5 (1): 114–8. doi:10.1159/000337319. PMC 3364094Freely accessible. PMID 22666198. 
  28. ^ Li Y, Zhang T, Ho C, Orange JS, Douglas SD, Ho WZ (December 2004). "Natural killer cells inhibit hepatitis C virus expression". J. Leukoc. Biol. 76 (6): 1171–9. doi:10.1189/jlb.0604372. PMID 15339939. 
  29. ^ Doskali M, Tanaka Y, Ohira M, Ishiyama K, Tashiro H, Chayama K, Ohdan H (March 2011). "Possibility of adoptive immunotherapy with peripheral blood-derived CD3⁻CD56+ and CD3+CD56+ cells for inducing antihepatocellular carcinoma and antihepatitis C virus activity". J. Immunother. 34 (2): 129–38. doi:10.1097/CJI.0b013e3182048c4e. PMID 21304407. 
  30. ^ Terunuma H, Deng X, Dewan Z, Fujimoto S, Yamamoto N (2008). "Potential role of NK cells in the induction of immune responses: implications for NK cell-based immunotherapy for cancers and viral infections". Int. Rev. Immunol. 27 (3): 93–110. doi:10.1080/08830180801911743. PMID 18437601. 
  31. ^ See DM, Tilles JG (1996). "alpha-Interferon treatment of patients with chronic fatigue syndrome". Immunol. Invest. 25 (1–2): 153–64. doi:10.3109/08820139609059298. PMID 8675231. 
  32. ^ Ojo-Amaize EA, Conley EJ, Peter JB (January 1994). "Decreased natural killer cell activity is associated with severity of chronic fatigue immune dysfunction syndrome". Clin. Infect. Dis. 18 Suppl 1: S157–9. doi:10.1093/clinids/18.Supplement_1.S157. PMID 8148445. 
  33. ^ Kida K, Isozumi R, Ito M (December 2000). "Killing of human Herpes virus 6-infected cells by lymphocytes cultured with interleukin-2 or -12". Pediatr Int. 42 (6): 631–6. doi:10.1046/j.1442-200x.2000.01315.x. PMID 11192519. 
  34. ^ Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA (October 2006). "Cancer regression in patients after transfer of genetically engineered lymphocytes". Science. 314 (5796): 126–9. doi:10.1126/science.1129003. PMC 2267026Freely accessible. PMID 16946036. 
  35. ^ Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, Jungbluth A, Gnjatic S, Thompson JA, Yee C (June 2008). "Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1". N. Engl. J. Med. 358 (25): 2698–703. doi:10.1056/NEJMoa0800251. PMC 3277288Freely accessible. PMID 18565862. 
  36. ^ "2008 Symposium Program & Speakers". Cancer Research Institute. 
  37. ^ http://www.telegraph.co.uk/earth/main.jhtml?xml=/earth/2008/06/18/scicanc118.xml[full citation needed]
  38. ^ Rotrosen D, Matthews JB, Bluestone JA (July 2002). "The immune tolerance network: a new paradigm for developing tolerance-inducing therapies". The Journal of Allergy and Clinical Immunology. 110 (1): 17–23. doi:10.1067/mai.2002.124258. PMID 12110811. 
  39. ^ Durham SR, Walker SM, Varga EM, Jacobson MR, O'Brien F, Noble W, Till SJ, Hamid QA, Nouri-Aria KT (August 1999). "Long-term clinical efficacy of grass-pollen immunotherapy". N. Engl. J. Med. 341 (7): 468–75. doi:10.1056/NEJM199908123410702. PMID 10441602. 
  40. ^ "Clinical Trials Search Results - Stanford University School of Medicine". med.stanford.edu. Retrieved 2016-04-03. 
  41. ^ Correale J, Farez M (February 2007). "Association between parasite infection and immune responses in multiple sclerosis". Annals of Neurology. 61 (2): 97–108. doi:10.1002/ana.21067. PMID 17230481. 
  42. ^ Croese J, O'neil J, Masson J, Cooke S, Melrose W, Pritchard D, Speare R (January 2006). "A proof of concept study establishing Necator americanus in Crohn's patients and reservoir donors". Gut. 55 (1): 136–7. doi:10.1136/gut.2005.079129. PMC 1856386Freely accessible. PMID 16344586. 
  43. ^ Reddy A, Fried B (January 2009). "An update on the use of helminths to treat Crohn's and other autoimmunune diseases". Parasitol. Res. 104 (2): 217–21. doi:10.1007/s00436-008-1297-5. PMID 19050918. 
  44. ^ Laclotte C, Oussalah A, Rey P, Bensenane M, Pluvinage N, Chevaux JB, Trouilloud I, Serre AA, Boucekkine T, Bigard MA, Peyrin-Biroulet L (December 2008). "[Helminths and inflammatory bowel diseases]". Gastroenterol. Clin. Biol. (in French). 32 (12): 1064–74. doi:10.1016/j.gcb.2008.04.030. PMID 18619749. 
  45. ^ Zaccone P, Fehervari Z, Phillips JM, Dunne DW, Cooke A (October 2006). "Parasitic worms and inflammatory diseases". Parasite Immunol. 28 (10): 515–23. doi:10.1111/j.1365-3024.2006.00879.x. PMC 1618732Freely accessible. PMID 16965287. 
  46. ^ a b Brooker S, Bethony J, Hotez PJ (2004). "Human Hookworm Infection in the 21st Century". Advances in Parasitology. 58: 197–288. doi:10.1016/S0065-308X(04)58004-1. ISBN 9780120317585. PMC 2268732Freely accessible. PMID 15603764. 
  47. ^ Fujiwara RT, Cançado GG, Freitas PA, Santiago HC, Massara CL, Dos Santos Carvalho O, Corrêa-Oliveira R, Geiger SM, Bethony J (2009). Yazdanbakhsh M, ed. "Necator americanus infection: a possible cause of altered dendritic cell differentiation and eosinophil profile in chronically infected individuals". PLoS Negl Trop Dis. 3 (3): e399. doi:10.1371/journal.pntd.0000399. PMC 2654967Freely accessible. PMID 19308259. 
  48. ^ Carvalho L, Sun J, Kane C, Marshall F, Krawczyk C, Pearce EJ (January 2009). "Review series on helminths, immune modulation and the hygiene hypothesis: mechanisms underlying helminth modulation of dendritic cell function". Immunology. 126 (1): 28–34. doi:10.1111/j.1365-2567.2008.03008.x. PMC 2632707Freely accessible. PMID 19120496. 
  49. ^ Fumagalli M, Pozzoli U, Cagliani R, Comi GP, Riva S, Clerici M, Bresolin N, Sironi M (June 2009). "Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions". J. Exp. Med. 206 (6): 1395–408. doi:10.1084/jem.20082779. PMC 2715056Freely accessible. PMID 19468064. 

External links[edit]