Editing DNA vaccine (section)

=== Helper T cell responses ===

[[Image:Antigen presentation.svg|thumb|right|Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells. Cytotoxic cells directly attack other cells carrying certain foreign or abnormal molecules on their surfaces. Helper T cells, or Th cells, coordinate immune responses by communicating with other cells. In most cases, T cells only recognize an antigen if it is carried on the surface of a cell by one of the body's own MHC, or major histocompatibility complex, molecules.]]
DNA immunization can raise multiple T<sub>H</sub> responses, including lymphoproliferation and the generation of a variety of [[cytokine]] profiles. A major advantage of DNA vaccines is the ease with which they can be manipulated to bias the type of T-cell help towards a TH1 or TH2 response.<ref name=Feltquate1997>{{cite journal | vauthors = Feltquate DM, Heaney S, Webster RG, Robinson HL | title = Different T helper cell types and antibody isotypes generated by saline and gene gun DNA immunization | journal = Journal of Immunology | volume = 158 | issue = 5 | pages = 2278–2284 | date = March 1997 | doi = 10.4049/jimmunol.158.5.2278 | pmid = 9036975 | s2cid = 41368723 | url = http://www.jimmunol.org/cgi/content/abstract/158/5/2278 | doi-access = free }}</ref> Each type has distinctive patterns of [[lymphokine]] and chemokine expression, specific types of [[immunoglobulins]], patterns of lymphocyte trafficking and types of [[innate immune response]]s.

==== Other types of T-cell help ====
The type of T-cell help raised is influenced by the delivery method and the type of immunogen expressed, as well as the targeting of different lymphoid compartments.<ref name=Alarcon1999 /><ref name=References1996>{{cite journal | vauthors = Boyle CM, Morin M, Webster RG, Robinson HL | title = Role of different lymphoid tissues in the initiation and maintenance of DNA-raised antibody responses to the influenza virus H1 glycoprotein | journal = Journal of Virology | volume = 70 | issue = 12 | pages = 9074–9078 | date = December 1996 | pmid = 8971047 | pmc = 191015 | doi = 10.1128/JVI.70.12.9074-9078.1996 }}</ref> Generally, saline needle injections (either IM or ID) tend to induce TH1 responses, while gene gun delivery raises TH2 responses.<ref name=Feltquate1997 /><ref name=References1996 /> This is true for intracellular and plasma membrane-bound antigens, but not for secreted antigens, which seem to generate TH2 responses, regardless of the method of delivery.<ref name="Sällberg1997">{{cite journal | vauthors = Sällberg M, Townsend K, Chen M, O'Dea J, Banks T, Jolly DJ, Chang SM, Lee WT, Milich DR | display-authors = 6 | title = Characterization of humoral and CD4+ cellular responses after genetic immunization with retroviral vectors expressing different forms of the hepatitis B virus core and e antigens | journal = Journal of Virology | volume = 71 | issue = 7 | pages = 5295–5303 | date = July 1997 | pmid = 9188598 | pmc = 191766 | doi = 10.1128/JVI.71.7.5295-5303.1997 }}</ref>

Generally the type of T-cell help raised is stable over time, and does not change when challenged or after subsequent immunizations that would normally have raised the opposite type of response in a naïve specimen.<ref name=Feltquate1997 /><ref name=References1996 /> However, Mor ''et al.''. (1995)<ref name=Mor1995 /> immunized and boosted mice with pDNA encoding the circumsporozoite protein of the mouse [[malaria]]l parasite ''[[Plasmodium yoelii]]'' (PyCSP) and found that the initial TH2 response changed, after boosting, to a TH1 response.

==== Basis for different types of T-cell help ====

How these different methods operate, the forms of antigen expressed, and the different profiles of T-cell help is not understood. It was thought that the relatively large amounts of DNA used in IM injection were responsible for the induction of TH1 responses. However, evidence shows no dose-related differences in TH type.<ref name=Feltquate1997 /> The type of T-cell help raised is determined by the differentiated state of [[antigen presenting cells]]. [[Dendritic cells]] can differentiate to secrete [[interleukin|IL-12]] (which supports TH1 cell development) or [[Interleukin-4 receptor|IL-4]] (which supports TH2 responses).<ref name=Banchereau1998>{{cite journal | vauthors = Banchereau J, Steinman RM | title = Dendritic cells and the control of immunity | journal = Nature | volume = 392 | issue = 6673 | pages = 245–252 | date = March 1998 | pmid = 9521319 | doi = 10.1038/32588 | s2cid = 4388748 | bibcode = 1998Natur.392..245B | author-link1 = Jacques Banchereau }}</ref> pDNA injected by needle is [[endocytosis|endocytosed]] into the dendritic cell, which is then stimulated to differentiate for TH1 [[cytokine]] (IL-12) production,<ref name=Jakob1998>{{cite journal | vauthors = Jakob T, Walker PS, Krieg AM, Udey MC, Vogel JC | title = Activation of cutaneous dendritic cells by CpG-containing oligodeoxynucleotides: a role for dendritic cells in the augmentation of Th1 responses by immunostimulatory DNA | journal = Journal of Immunology | volume = 161 | issue = 6 | pages = 3042–3049 | date = September 1998 | doi = 10.4049/jimmunol.161.6.3042 | pmid = 9743369 | s2cid = 35107733 | url = http://www.jimmunol.org/cgi/content/abstract/161/6/3042 | doi-access = free }}</ref> while the gene gun bombards the DNA directly into the cell, thus bypassing TH1 stimulation.

==== Practical uses of polarised T-cell help ====

Polarisation in T-cell help is useful in influencing [[allergic]] responses and [[autoimmune diseases]]. In autoimmune diseases, the goal is to shift the self-destructive TH1 response (with its associated cytotoxic T cell activity) to a non-destructive TH2 response. This has been successfully applied in [[predisease]] [[Priming (immunology)|priming]] for the desired type of response in [[preclinical]] [[Model organism|models]]<ref name=Robinson2000 /> and is somewhat successful in shifting the response for an established disease.<ref name=Raz1996>{{cite journal | vauthors = Raz E, Tighe H, Sato Y, Corr M, Dudler JA, Roman M, Swain SL, Spiegelberg HL, Carson DA | display-authors = 6 | title = Preferential induction of a Th1 immune response and inhibition of specific IgE antibody formation by plasmid DNA immunization | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 10 | pages = 5141–5145 | date = May 1996 | pmid = 8643542 | pmc = 39421 | doi = 10.1073/pnas.93.10.5141 | doi-access = free | bibcode = 1996PNAS...93.5141R }}</ref>