Editing Immune system (section)

== Manipulation in medicine ==

[[File:Dexamethasone structure.svg|thumb|right|upright=0.9 |alt=Skeletal structural formula of dexamethasone, C22 H29 F O5 |Skeletal structural formula of the [[immunosuppressive drug]] [[dexamethasone]]]]
The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and [[transplant rejection]], and to stimulate protective responses against pathogens that largely elude the immune system (see [[#Active memory and immunization|immunization]]) or cancer.{{sfn | Sompayrac | 2019 | pp=83–85}}

=== Immunosuppression ===
[[Immunosuppressive drug]]s are used to control autoimmune disorders or [[inflammation]] when excessive tissue damage occurs, and to prevent rejection after an [[organ transplant]].{{sfn|Ciccone |2015 |loc = Chapter [https://books.google.com/books?id=Te1vCAAAQBAJ&q=%22immunosuppressive+drugs%22+autoimmune+tissue+damage&pg=PA625 37]}}<ref name= Taylor>{{cite journal | vauthors = Taylor AL, Watson CJ, Bradley JA | title = Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy | journal = Critical Reviews in Oncology/Hematology | volume = 56 | issue = 1 | pages = 23–46 | date = Oct 2005 | pmid = 16039869 | doi = 10.1016/j.critrevonc.2005.03.012 }}</ref>

[[Anti-inflammatory]] drugs are often used to control the effects of inflammation. [[Glucocorticoid]]s are the most powerful of these drugs and can have many undesirable [[adverse effect|side effects]], such as [[central obesity]], [[hyperglycemia]], and [[osteoporosis]].<ref>{{cite journal | vauthors = Barnes PJ | title = Corticosteroids: the drugs to beat | journal = European Journal of Pharmacology | volume = 533 | issue = 1–3 | pages = 2–14 | date = Mar 2006 | pmid = 16436275 | doi = 10.1016/j.ejphar.2005.12.052 }}</ref> Their use is tightly controlled. Lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as [[methotrexate]] or [[azathioprine]].

[[Chemotherapy|Cytotoxic drugs]] inhibit the immune response by killing dividing cells such as activated T cells. This killing is indiscriminate and other [[constantly dividing cells]] and their organs are affected, which causes toxic side effects.<ref name= Taylor /> Immunosuppressive drugs such as [[cyclosporin]] prevent T cells from responding to signals correctly by inhibiting [[signal transduction]] pathways.<ref>{{cite journal | vauthors = Masri MA | title = The mosaic of immunosuppressive drugs | journal = Molecular Immunology | volume = 39 | issue = 17–18 | pages = 1073–77 | date = Jul 2003 | pmid = 12835079 | doi = 10.1016/S0161-5890(03)00075-0 }}</ref>

=== Immunostimulation ===
{{Main|Immunostimulant|Immunotherapy|Vaccination}}
Claims made by marketers of various products and [[Alternative medicine|alternative health providers]], such as [[Chiropractic|chiropractors]], [[Homeopathy|homeopaths]], and [[Acupuncture|acupuncturists]] to be able to stimulate or "boost" the immune system generally lack meaningful explanation and evidence of effectiveness.<ref>{{cite magazine | vauthors = Hall H |author-link1 = Harriet Hall |date=July–August 2020 |title=How You Can Really Boost Your Immune System |url=https://skepticalinquirer.org/2020/06/how-you-can-really-boost-your-immune-system/ |url-status= |magazine=[[Skeptical Inquirer]] |location=Amherst, New York |publisher=[[Center for Inquiry]] |archive-url=https://web.archive.org/web/20210121161902/https://skepticalinquirer.org/2020/06/how-you-can-really-boost-your-immune-system/ |archive-date=21 January 2021 |access-date=21 January 2021}}</ref>

===Vaccination===
{{Further|Vaccination}}
[[File:Polio Vaccination - Egypt (16868521330).jpg|right|thumb|Polio vaccination in Egypt|alt= A child receiving drops of polio vaccine in her mouth]]
Long-term ''active'' memory is acquired following infection by activation of B and T cells. Active immunity can also be generated artificially, through [[vaccination]]. The principle behind vaccination (also called [[immunization]]) is to introduce an [[antigen]] from a pathogen to stimulate the immune system and develop [[specific immunity]] against that particular pathogen without causing disease associated with that organism.{{sfn | Reece | 2011 | p=965}} This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With infectious disease remaining one of the leading causes of death in the human population, vaccination represents the most effective manipulation of the immune system mankind has developed.{{sfn| Janeway |2005 |p=}}<ref>[https://www.who.int/healthinfo/bod/en/index.html Death and DALY estimates for 2002 by cause for WHO Member States.] {{Webarchive|url=https://web.archive.org/web/20081021133659/http://www.who.int/healthinfo/bod/en/index.html |date=21 October 2008 }} [[World Health Organization]]. Retrieved on 1 January 2007.</ref>

Many vaccines are based on [[non-cellular life|acellular]] components of micro-organisms, including harmless [[toxin]] components.{{sfn | Reece | 2011 | p=965}} Since many antigens derived from acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional [[Immunologic adjuvant|adjuvants]] that activate the [[antigen-presenting cell]]s of the innate immune system and maximize [[immunogenicity]].<ref>{{cite journal | vauthors = Singh M, O'Hagan D | title = Advances in vaccine adjuvants | journal = Nature Biotechnology | volume = 17 | issue = 11 | pages = 1075–81 | date = Nov 1999 | pmid = 10545912 | doi = 10.1038/15058 | s2cid = 21346647 | doi-access = free }}</ref>

=== Tumor immunology ===
{{Further|Cancer immunology}}

Another important role of the immune system is to identify and eliminate [[tumor]]s. This is called '''immune surveillance'''.<!-- for redirect --> The ''transformed cells'' of tumors express [[antigen#Tumor antigens|antigens]] that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources;<ref name = anderson>{{cite journal | vauthors = Andersen MH, Schrama D, Thor Straten P, Becker JC | title = Cytotoxic T cells | journal = The Journal of Investigative Dermatology | volume = 126 | issue = 1 | pages = 32–41 | date = Jan 2006 | pmid = 16417215 | doi = 10.1038/sj.jid.5700001 | doi-access = free }}</ref> some are derived from [[oncogenic]] viruses like [[human papillomavirus]], which causes cancer of the [[cervical cancer|cervix]],<ref>{{cite journal | vauthors = Boon T, van der Bruggen P | title = Human tumor antigens recognized by T lymphocytes | journal = The Journal of Experimental Medicine | volume = 183 | issue = 3 | pages = 725–29 | date = Mar 1996 | pmid = 8642276 | pmc = 2192342 | doi = 10.1084/jem.183.3.725 }}</ref> [[vulva cancer|vulva]], [[vaginal cancer|vagina]], [[penis cancer|penis]], [[anal cancer|anus]], [[oropharynx|mouth, and throat]],<ref name=Lj2014>{{cite journal | vauthors = Ljubojevic S, Skerlev M | title = HPV-associated diseases | journal = Clinics in Dermatology | volume = 32 | issue = 2 | pages = 227–34 | year = 2014 | pmid = 24559558 | doi = 10.1016/j.clindermatol.2013.08.007 }}</ref> while others are the organism's own proteins that occur at low levels in normal cells but reach high levels in tumor cells. One example is an enzyme called [[tyrosinase]] that, when expressed at high levels, transforms certain skin cells (for example, [[melanocyte]]s) into tumors called [[melanoma]]s.<ref>{{cite journal | vauthors = Castelli C, Rivoltini L, Andreola G, Carrabba M, Renkvist N, Parmiani G | title = T-cell recognition of melanoma-associated antigens | journal = Journal of Cellular Physiology | volume = 182 | issue = 3 | pages = 323–31 | date = Mar 2000 | pmid = 10653598 | doi = 10.1002/(SICI)1097-4652(200003)182:3<323::AID-JCP2>3.0.CO;2-# | s2cid = 196590144 }}</ref><ref name = romera>{{cite book | vauthors = Romero P, Cerottini JC, Speiser DE | title = The Human T Cell Response to Melanoma Antigens | volume = 92 | pages = 187–224 | year = 2006 | pmid = 17145305 | doi = 10.1016/S0065-2776(06)92005-7 | isbn = 978-0-12-373636-9 | series = Advances in Immunology }}</ref> A third possible source of [[tumor antigen]]s are proteins normally important for regulating [[cell growth]] and survival, that commonly mutate into cancer inducing molecules called [[oncogene]]s.<ref name = anderson /><ref name = guevara>{{cite journal | vauthors = Guevara-Patiño JA, Turk MJ, Wolchok JD, Houghton AN | title = Immunity to cancer through immune recognition of altered self: studies with melanoma | volume = 90 | pages = 157–77 | year = 2003 | pmid = 14710950 | doi = 10.1016/S0065-230X(03)90005-4 | isbn = 978-0-12-006690-2 | journal = Advances in Cancer Research }}</ref><ref>{{cite journal | vauthors = Renkvist N, Castelli C, Robbins PF, Parmiani G | title = A listing of human tumor antigens recognized by T cells | journal = Cancer Immunology, Immunotherapy | volume = 50 | issue = 1 | pages = 3–15 | date = Mar 2001 | pmid = 11315507 | doi = 10.1007/s002620000169 | s2cid = 42681479 | doi-access = free | pmc = 11036832 }}</ref>

[[File:Macs killing cancer cell.jpg|thumb|right|upright=1.15 |alt=See caption |[[Macrophage]]s have identified a cancer cell (the large, spiky mass). Upon fusing with the cancer cell, the macrophages (smaller white cells) inject toxins that kill the tumor cell. [[Immunotherapy]] for the treatment of [[Cancer#Immunotherapy|cancer]] is an active area of medical research.<ref>{{cite journal  |vauthors=Morgan RA, Dudley ME, Wunderlich JR, etal |title=Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes |journal=Science |volume=314 |issue=5796 |pages=126–29 |date=October 2006 |pmid=16946036 |pmc=2267026 |doi=10.1126/science.1129003|bibcode = 2006Sci...314..126M }}</ref>]]

The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells.<ref name = romera /><ref>{{cite journal | vauthors = Gerloni M, Zanetti M | s2cid = 25182066 | title = CD4 T cells in tumor immunity | journal = Springer Seminars in Immunopathology | volume = 27 | issue = 1 | pages = 37–48 | date = Jun 2005 | pmid = 15965712 | doi = 10.1007/s00281-004-0193-z | url = https://zenodo.org/record/1066157 }}</ref> [[Tumor antigen]]s are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal.<ref name = seliger>{{cite journal | vauthors = Seliger B, Ritz U, Ferrone S | title = Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation | journal = International Journal of Cancer | volume = 118 | issue = 1 | pages = 129–38 | date = Jan 2006 | pmid = 16003759 | doi = 10.1002/ijc.21312 | s2cid = 5655726 | doi-access = free }}</ref> NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumors.<ref>{{cite journal | vauthors = Hayakawa Y, Smyth MJ | title = Innate immune recognition and suppression of tumors | volume = 95 | pages = 293–322 | year = 2006 | pmid = 16860661 | doi = 10.1016/S0065-230X(06)95008-8 | isbn = 978-0-12-006695-7 | journal = Advances in Cancer Research }}</ref> Sometimes antibodies are generated against tumor cells allowing for their destruction by the [[complement system]].<ref name = guevara />

Some tumors evade the immune system and go on to become cancers.<ref name="Syn-2017">{{cite journal | vauthors = Syn NL, Teng MW, Mok TS, Soo RA | title = De-novo and acquired resistance to immune checkpoint targeting | journal = The Lancet. Oncology | volume = 18 | issue = 12 | pages = e731–e741 | date = December 2017 | pmid = 29208439 | doi = 10.1016/s1470-2045(17)30607-1 }}</ref><ref name = selig>{{cite journal | vauthors = Seliger B | title = Strategies of tumor immune evasion | journal = BioDrugs | volume = 19 | issue = 6 | pages = 347–54 | year = 2005 | pmid = 16392887 | doi = 10.2165/00063030-200519060-00002 | s2cid = 1838144 }}</ref> Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells.<ref name = seliger /><ref name="Syn-2017" /> Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine [[TGF beta|TGF-β]], which suppresses the activity of [[macrophage]]s and [[lymphocyte]]s.<ref name="Syn-2017" /><ref>{{cite journal | vauthors = Frumento G, Piazza T, Di Carlo E, Ferrini S | title = Targeting tumor-related immunosuppression for cancer immunotherapy | journal = Endocrine, Metabolic & Immune Disorders Drug Targets | volume = 6 | issue = 3 | pages = 233–7 | date = September 2006 | pmid = 17017974 | doi = 10.2174/187153006778250019 }}</ref> In addition, [[immune tolerance|immunological tolerance]] may develop against tumor antigens, so the immune system no longer attacks the tumor cells.<ref name="Syn-2017" /><ref name = selig />

Paradoxically, macrophages can promote tumor growth<ref>{{cite journal|vauthors=Stix G |title=A malignant flame. Understanding chronic inflammation, which contributes to heart disease, Alzheimer's and a variety of other ailments, may be a key to unlocking the mysteries of cancer |journal=Scientific American |volume=297 |issue=1 |pages=60–67 |date=Jul 2007 |pmid=17695843 |doi=10.1038/scientificamerican0707-60 |url=http://podcast.sciam.com/daily/pdf/sa_d_podcast_070619.pdf |url-status=dead |archive-url=https://web.archive.org/web/20110716015048/http://podcast.sciam.com/daily/pdf/sa_d_podcast_070619.pdf |archive-date=16 July 2011 |bibcode=2007SciAm.297a..60S }}</ref> when tumor cells send out cytokines that attract macrophages, which then generate cytokines and growth factors such as [[Tumor necrosis factor alpha|tumor-necrosis factor alpha]] that nurture tumor development or promote stem-cell-like plasticity.<ref name="Syn-2017" /> In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks [[metastasis]] and thereby assists spread of cancer cells.<ref name="Syn-2017" /> Anti-tumor M1 macrophages are recruited in early phases to tumor development but are progressively differentiated to M2 with pro-tumor effect, an immunosuppressor switch. The hypoxia reduces the cytokine production for the anti-tumor response and progressively macrophages acquire pro-tumor M2 functions driven by the tumor microenvironment, including IL-4 and IL-10.<ref>{{cite journal | vauthors = Cervantes-Villagrana RD, Albores-García D, Cervantes-Villagrana AR, García-Acevez SJ | title = Tumor-induced Neurogenesis and Immune Evasion as Targets of Innovative Anti-Cancer Therapies | journal = Signal Transduct Target Ther | volume = 5 | issue = 1 | pages = 99 | date = 18 June 2020 | pmid = 32555170 | pmc = 7303203 | doi = 10.1038/s41392-020-0205-z }}</ref> [[Cancer immunotherapy]] covers the medical ways to stimulate the immune system to attack cancer tumors.<ref name="pmid26325031">{{cite journal |vauthors=Yang Y |title=Cancer immunotherapy: harnessing the immune system to battle cancer |journal=The Journal of Clinical Investigation |volume=125 |issue=9 |pages=3335–7 |date=September 2015 |pmid=26325031 |pmc=4588312 |doi=10.1172/JCI83871 }}</ref>

=== Predicting immunogenicity ===
Some drugs can cause a neutralizing immune response, meaning that the immune system produces [[neutralizing antibodies]] that counteract the action of the drugs, particularly if the drugs are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are typically larger than 6000 [[Dalton (unit)|Da]]).<ref name="Baker2010">{{cite journal | vauthors = Baker MP, Reynolds HM, Lumicisi B, Bryson CJ | title = Immunogenicity of protein therapeutics: The key causes, consequences and challenges | journal = Self/Nonself | volume = 1 | issue = 4 | pages = 314–322 | date = October 2010 | pmid = 21487506 | pmc = 3062386 | doi = 10.4161/self.1.4.13904 }}</ref> In some cases, the drug itself is not immunogenic, but may be co-administered with an immunogenic compound, as is sometimes the case for [[paclitaxel|Taxol]]. Computational methods have been developed to predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug treatments. Early techniques relied mainly on the observation that [[hydrophile|hydrophilic]] [[amino acid]]s are overrepresented in [[epitope]] regions than [[hydrophobe|hydrophobic]] amino acids;<ref name="Welling">{{cite journal | vauthors = Welling GW, Weijer WJ, van der Zee R, Welling-Wester S | title = Prediction of sequential antigenic regions in proteins | journal = FEBS Letters | volume = 188 | issue = 2 | pages = 215–18 | date = Sep 1985 | pmid = 2411595 | doi = 10.1016/0014-5793(85)80374-4 | doi-access = free | bibcode = 1985FEBSL.188..215W }}</ref> however, more recent developments rely on [[machine learning]] techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a [[training set]].<ref name="Sollner">{{cite journal | vauthors = Söllner J, Mayer B | title = Machine learning approaches for prediction of linear B-cell epitopes on proteins | journal = Journal of Molecular Recognition | volume = 19 | issue = 3 | pages = 200–08 | year = 2006 | pmid = 16598694 | doi = 10.1002/jmr.771 | s2cid = 18197810 }}</ref> A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells.<ref name="Saha">{{cite journal | vauthors = Saha S, Bhasin M, Raghava GP | title = Bcipep: a database of B-cell epitopes | journal = BMC Genomics | volume = 6 | pages = 79 | year = 2005 | pmid = 15921533 | pmc = 1173103 | doi = 10.1186/1471-2164-6-79 | doi-access = free }}</ref> The emerging field of [[bioinformatics]]-based studies of immunogenicity is referred to as ''[[immunoinformatics]]''.<ref name="Flower">{{cite journal | vauthors = Flower DR, Doytchinova IA | title = Immunoinformatics and the prediction of immunogenicity | journal = Applied Bioinformatics | volume = 1 | issue = 4 | pages = 167–76 | year = 2002 | pmid = 15130835 }}</ref> [[Immunoproteomics]] is the study of large sets of proteins ([[proteomics]]) involved in the immune response.<ref name="pmid31356379">{{cite journal |vauthors=Kanduc D |title=From hepatitis C virus immunoproteomics to rheumatology via cross-reactivity in one table |journal=Current Opinion in Rheumatology |volume=31 |issue=5 |pages=488–492 |date=September 2019 |pmid=31356379 |doi=10.1097/BOR.0000000000000606|s2cid=198982175 }}</ref>