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Advances in Immunology:
Role of T-Helper Lymphocyte Subsets
cells, T-suppressor cells, and didiasis, and leishmaniasis) ini- cent studies have implicated TH2
Keith A. Hnilica, DVM cytotoxic T cells. In 1986, it tiate a TH1 response, but if the cells in the development of
Donna W. Angarano, DVM was discovered that T-helper infection is not completely atherosclerosis.22
Diplomate, ACVD cells could be further subdivid- cleared, the immune reaction
ed into two distinct subsets: may switch to the T H 2 re- Factors for Subset
College of Veterinary Medicine TH1 and TH2 cells.1 These func- sponse. 5–8 When the T H 2 re- Proliferation
Auburn University tionally polar subsets are princi- sponse becomes the predomi- Multiple factors (e.g., genet-
Auburn, Alabama pal regulators of the immune nant reaction in an infection, ics, antigen dose and structure,
system—they direct the im- widespread tissue involvement and antigen-presenting cells)
mune response.1–3 results and severe systemic dis- influence the stimulation of
W
ith the advances in The two fundamental types ease often follows.5–7 TH1 lym- specific T-helper cell subsets1–4
medical technolo- of immune response are innate phocytes have been implicated (Figure 1). Antigenic factors are
gy, practitioners and acquired immunity. Innate in various pathologic processes, among the most important.3,4
often find themselves practicing immunity involves phagocytes including autoimmune diseases The structure of the antigen, the
medicine on the cellular and (macrophages and neutrophils), (e.g., multiple sclerosis, insulin- route of presentation, and the
molecular levels—especially in which recognize foreign anti- dependent diabetes mellitus, dose are all critical in T-cell pro-
immunology. AIDS has been a gens nonspecifically. Innate im- and rheumatoid arthritis), graft motion, but the role of each
major driving force in immunol- munity is the initial immune re-
ogy; as a result, many facets of sponse and requires no previous
■ T-helper lymphocytes can be divided into two
the immune system have been antigen exposure to be activat-
functionally distinct groups: T-helper 1 and T-
better characterized. T lympho- ed. Acquired immunity is an
KEY POINTS
helper 2 lymphocytes.
cytes are only one element of antigen-specific response that
needs previous exposure to the
■ T-helper 1 lymphocytes stimulate cell-mediated
the immune system, but they
and innate immunity, whereas T-helper 2 lym-
play a significant role in dis- foreign antigen. In general, TH1
phocytes stimulate humoral immunity.
ease. cells stimulate innate and cell-
The immune system is so mediated immunity, and TH2 ■ It is now possible to develop novel therapies
cells stimulate humoral immu-
that alter T-helper lymphocyte subset response.
complex that it is often an over-
whelming task to keep abreast nity, eosinophils, and mast
of changes. This column re- cells.1–3 When stimulated, each rejection, inflammatory bowel antigenic factor remains poorly
views the recent developments T-helper cell subset inhibits the disease, and psoriasis.9–16 characterized.2–4 Antigen-pre-
in T-cell function, with special development of the alternative The TH2 response may be a senting cells survey the local
attention to the T-helper cell subset; thus, diseases typically modification made by the host’s tissue environment and process
subsets (T-helper 1 [TH1] and involve either a TH1 or a TH2 re- immune system to prevent dam- antigens for presentation to the
2 [TH2] cells) and their role in sponse.1,2,4 aging immune reactions (from appropriate component of the
normal immune responses as The TH1 response is most ef- the TH1 response) in chronic immune system. Specific anti-
well as aberrant T-lymphocyte ficient at defending the host disease. TH2 lymphocytes are gen-presenting cells process
function. from infection. Bacteria and the primary effector cells in aller- and present antigens differently.
viruses usually initiate a TH1 re- gy, parasitic infection, lupus, TH1 cells are preferentially acti-
T-Helper sponse, which promotes an im- shingles, and AIDS.5,8–11,17–21 In vated by macrophages, and TH2
Lymphocyte Subsets mune reaction that resolves the HIV-positive individuals, the TH2 cells are stimulated by tissue-
T lymphocytes are classified infection.2,3 Some infectious dis- lymphocyte response leads to a specific dendritic cells.
into functional groups: T-helper eases (e.g., AIDS, leprosy, can- more rapid onset of AIDS.5 Re- Atopic dermatitis serves as a
The Compendium January 1997 Small Animal
Genetics
Antigen characteristics (parasites)
T-helper 1 T-helper T-helper 2 Antigen dose, route
Antigen-presenting cells (Langerhans’
precursor
cells)
Cytokines (IL-4, IL-5, IL-10)
Figure 1—The differentiation of T-helper lymphocytes depends on multiple factors, including genetics, antigen characteristics, and mi-
croenvironment. IL = interleukin.
TABLE THREE
Immune Response Modifiers
Immune Modulators Immunologic Effect Possible Application
Specific
Interferon-γ Stimulates innate immunity; promotes Atopic dermatitis; infectious disease;
the TH1 response; inhibits the TH2 adjuvant therapy for neoplasia
response
Interleukin-12 Promotes the TH1 response; inhibits Convert immune response from
the TH2 response TH2 to TH1; chronic infections
Nonspecific
Ultraviolet light Inhibits Langerhans’ cells and the Atopic dermatitis; inflammatory
epidermal immune response dermatosis
Levamisole Alters T cell, monocyte, and neutrophil Limited efficacy in veterinary medicine
function
als treated with injectable inter- These preliminary results are en- the switch to the protective TH1 Staphylococcal vaccines 1
feron-γ improved substantially couraging and suggest that spe- subset.6 In mice, chronic leish- have been used successfully
within 14 days and continued to cific modulation of the immune maniasis infection resolved with (50% response) to treat dogs
experience relief from symp- system may be used to treat IL-12 treatment. 6 The IL-12 with recurrent idiopathic bacte-
toms during treatment.21 Inter- common diseases. may have switched the TH2 re- rial pyoderma and staphylococ-
feron-γ is a TH1 cytokine that in- With chronic infectious dis- sponse associated with chronic cal hypersensitivity.23 During
hibits the exaggerated T H 2 eases involving a TH2 response disease to the protective TH1 treatment, elevated levels of
response in allergy. Patients had that leads to systemic disease response, thereby promoting TH1 cytokines (IL-1, IL-2, and
minimal side effects during the and patient decompensation, resolution of the infection. In interferon-γ) can be identified.24
6-week course of treatment; induced T-helper subset switch- diseases in which the TH2 re- This apparent stimulation of the
however, most had relapses ing can be useful. Cytokines sponse is predominant but inef- TH1 response is associated with
when treatment was discontin- that are produced by and pro- fective (leishmaniasis, AIDS, clinical improvement. As more
ued.21 Interferon-γ is expensive mote the TH1 cells inhibit TH2 candidiasis, and leprosy), IL-12 clinical trials are performed, ad-
and requires frequent injections. cells. IL-2 and IL-12 promote may be clinically useful. ditional methods that modulate
Small Animal The Compendium January 1997
References
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Paradigms lost? Immunol
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regulation of antimicrobial im-
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hypersensitivities. Curr Opin
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5. Romagnani S, Maggi E: T H 1
and TH2 responses in AIDS.
Curr Opin Immunol 4:616–622,
1994.
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Insights from leprosy. J Invest
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7. Romani L, Mencacci A, Ceni E,
et al: CD4+ subset expression
in murine candidiasis. J Immunol
150:925-931, 1993.
Figure 3—Cutaneous allergy immune response. Langerhans’ cells process and present the antigen to
8. Zhang Y, Cosyns M, Levin MI,
the T-helper 2 (TH2 ) lymphocytes. These lymphocytes produce cytokines (IL-4, IL-5, IL-10, and IL-
et al: Cytokine production in
13), which activate B lymphocytes (B ) and stimulate IgE production. The IgE is bound to the surface varicella zoster virus-stimulated
of the Langerhans’ cells (which enhances antigen recognition) and mast cells (which stimulates aller- limiting dilution lymphocyte
gen-specific degranulation). Mast cells, when stimulated, produce IL-4, which activates more TH2 cultures. Clin Exp Immunol
cells. Keratinocytes injured from the local inflammation and excoriation produce additional inflam- 98:128–133, 1994.
matory mediators. PG = prostaglandin. (From Hnilica KA: The TH2 immune response and the 9. Brett C, Lafferty KJ: The
pathogenesis of allergy. Vet Allergy Clin Immunol 4(4):129, 1996. Modified with permission. ) TH1/TH2 balance in autoimmu-
nity. Curr Opin Immunol 7:793–
798, 1995.
10. Liblau R, Singer S, McDevitt H:
the T-helper cell response may sponse (Table Three). Most of tors is not completely under- TH1 and TH2 CD4+ T cells in
be identified. these compounds cause non- stood; however, T-helper cells the pathogenesis of organ-
Human atopic dermatitis can specific activation of the innate may be involved. specific autoimmune diseases.
Immunol Today 16:34–38,
be treated effectively with cy- immune response. Levamisole is
1995.
closporine, which rapidly allevi- an anthelmintic that activates T Conclusion 11. Klinman DM, Steinberg AD: In-
ates symptoms.20,21 Cyclosporine cells, monocytes, and neu- The identification of T-helper quiry into murine and human
suppresses T-cell function and trophils. It has been used to treat lymphocyte subsets in disease lupus. Immunol Rev 144:157–
downregulates cytokine produc- many diseases but with limited has provided a greater under- 193, 1995.
12. Hafler DA, Weiner HL: Immuno-
tion.20 Unfortunately, however, success.25 A derivative of the aloe standing of the intricate interac-
logic mechanism and therapy in
clinical signs return rapidly when plant, acemannan, seems to pre- tions of the immune system. As multiple sclerosis. Immunol
treatment is discontinued, and dominantly stimulate macro- more diseases are classified on Rev 144:75–107, 1995.
side effects include renal failure phages.25 Results were inconsis- the basis of their lymphocyte re- 13. Mani RN, Elliott MI, Brennan
and hepatic toxicity. Clinical tri- tent when acemannan was used action patterns, novel therapies FM, et al: Monoclonal anti-TNF
alpha antibody as a probe of
als are currently under way to to treat such disorders as de- can be used to alter the funda-
pathogenesis and therapy of
evaluate the effectiveness of a layed wound healing, viral infec- mental immune response asso- rheumatoid disease. Immunol
low dose of cyclosporine used tions (feline leukemia virus and ciated with each disorder. These Rev 144:194–223, 1995.
over a prolonged period to con- feline immunodeficiency virus), new treatments allow practition- 14. Kupiec-Weglinski JW, Wasows-
trol allergic disease.20,21 and tumors (e.g., fibrosarcoma, ers to guide the immune re- ka B, Papp I, et al: CD4 mAB
therapy modulates alloantibody
Immune modulators are used lymphoma, and mast cell tu- sponse toward the optimum re-
production and intracardiac
for various diseases in an at- mors).25 The mechanism of ac- action pattern for any given graft deposition in association
tempt to boost the immune re- tion for most immune modula- disease. with selective inhibition of TH1
The Compendium January 1997 Small Animal