Definition

Delayed type hypersensitivity (DTH) reactions are antigen-specific, cell-mediated immune responses which, depending on the antigen involved, mediate beneficial (resistance to viruses, bacteria, fungi, and tumors) or harmful (allergic dermatitis, autoimmunity) aspects of immune function. Cutaneous DTH reactions are initiated when CD4 memory T cells are activated by Langerhans cells and other antigen-presenting cells in the skin. Upon activation, CD4 T cells release inflammatory mediators which recruit effector cells to the site of antigen administration. While the monocyte/macrophage is thought to be the major effector cell in this model, CD8+ cytolytic T cells, and NK cells are also thought to serve as effector cells in DTH reactions. Activated effector cells mount an inflammatory response which results in the elimination of antigen and the extravasation of plasma accompanied by selling at the site of challenge. The magnitude of the response to the antigen is measured as an increase in swelling at the site of challenge (e.g. as seen during the development of a tuberculin skin reaction).

Aspect of allostatic load measured by DTH response

The DTH response represents a cumulative measure of allostatic load as reflected in the breakdown of an important arm of the immune response, i.e., cell-mediated immunity (CMI). The endocrine and immunologic mechanisms which mediate this breakdown are currently under investigation.

Measurement of DTH

DTH responses to representative test antigens can be measured with the Multitest CMI (Pasteur Merieux Connaught, Swiftwater, PA). This test uses seven antigens: tuberculin, tetanus, diphtheria, Streptococcus, Candida, Trichophyton, and Proteus to test for cutaneous DTH responses in humans. The test is administered by pressing the antigen heads of the Multitest applicator firmly onto the volar surface of the lower arm. Applicator tips at the surface of each head, penetrate the epidermis depositing antigen into the epidermis and the dermis. A positive reaction to an antigen is manifest as a swelling at the site of administration. Indurations greater than 2mm at 48 hours are considered a positive reaction. Responses are scored to indicate 1) the number of positive responses (Number of Positive Antigens), 2) the size of each induration, which is the mean of measurements made across two diameters at right angles (Average Induration), and 3) the sum of the average induration scores (Total Induration Score).

The DTH response as a predictor of disease

A loss of DTH responsivity serves as an indicator of deterioration in cell-mediated immune function. Recently, a decrease in DTH responses to standard antigens, such as those used in the CMI test described above, has been used as an independent marker for disease progressin in HIV infected individuals (1, 2).

The DTH response and psychosocial factors

Recent evidence suggests that a decrease in the ability to mount DTH reactions may serve as marker for the detrimental effects of increased allostatic load on immune function. For example, Dhabhar & McEwen (1996) have shown that chronic stress administered to rats for a period of 3 to 5 weeks results in a significant suppression of a cutaneous DTH response (3). A chronic stress-induced decrease in the ability of the animal to mobilize leukocytes to site of immune challenge may be one of the factors mediating this chronic stress-induced suppression of cutaneous DTH. Furthermore, Sephton et al. (1997) have shown that in breast cancer patients, those individuals experiencing increased allostatic load (as reflected in higher mean circadian cortisol levels, greater depression scores (CESD) and greater mood disturbance (POMS)) show significantly lower cutaneous DTH (4, 5). This suggests that the DTH response is also sensitive to the effects psychosocial factors (detrimental effects of chronic stress in this case) in humans. Studies which examine the neuroendocrine and immune mechanisms by which psychosocial factors may influence cell-mediated immunity in vivo are currently in progress (Dhabhar, Sephton, McEwen, & Spiegel).

References

Huebner R.E., Schein M.F., Hall C.A., and Barnes S.A. 1994. Delayed-type hypersensitivity energy in human immunodeficiency virus-infected persons screened for infection with Mycobacterium tuberculosis. Clin. Infectious Dis. 19:26.

Gordin F.M., Hartigan P.M., Klimas N.G., Zolla-Pazner S.B., Simberkoff M.S., and Hamilton J.D. 1994. Delayed-typed hypersensitivity skin tests are an independent predictor of human immunodeficiency virus disease progression. Department of veterans affairs cooperative study group. J. Infectious Dis. 169:893.

Dhabhar F.S., and McEwen B.S. 1996b. Moderate stress enhances, and chronic stress suppresses, cell-mediated immunity in vivo. Society for Neuroscience Meeting, Washington, DC, Vol. 22, Abstr. 536.3. Society for Neuroscience Meeting, Washington, DC, Vol. 22, Abstr. 536.3. 1350.

Sephton S.E., Dhabhar F.S., McEwen B.S., and Spiegel D. 1997. Suppression of antigen-specific cell-mediated immunity is linked to higher cortisol and mood disturbance in advanced breast cancer patients. Gordon Conference in Neuro-Endocrine-Immunology.