The Study of Simple Chemicals in Animals and Man: Mechanisms of Contact Sensitivity

October 2012 | Volume 11 | Issue 10 | Original Article | 1166 | Copyright © October 2012

When simple chemical are applied to the skin, a series of events ensues that under some conditions ultimately results in contact sensitivity (CS), a proven cell-mediated immune response (CMI). Since the discovery of CMI using picryl-Cl (PCl) in 1942, we have learned a great deal on the cellular mechanisms involved in CS, including the potential to treat warts, skin cancer, autoimmune disorders, and allergies. In this review we summarize some of the basic mechanisms of both the innate and acquired immune systems involved in CS.

J Drugs Dermatol. 2012;11(10):1166-1173.


Landsteiner and Chase are generally credited with the first conscious discovery of cell-mediated immunity (CMI) with the contact sensitizer picryl chloride (PCL) in 1942. Peritoneal exudate, which is what Landsteiner and Chase used to elicit CMI, is predominantly bone marrow derived cells (macrophages and dendritic cells) and only a minority are lymphocytes. The cellular nature of this exudate was both bone marrow derived cells and lymphocytes, and both of these cells are necessary to elicit CMI (vide infra).1 Merrill (Figure 1), a true scholar, always gave credit to others for the discovery of CMI, especially James Murphy, with whom he overlapped during his early years at the Rockefeller. More recently, Silverstein has reemphasized Murphy's seminal work as identifying the importance of the lymphocyte in resistance to cancer.2 However, this earlier work, while important, cannot be construed to have identified CMI because resistance is not synonymous with immunity.3 Clayton has also credited Landsteiner and Chase for the original discovery of CMI and Mitcheson and Gowans for their work done in the 1950s and 1960s in the exploration of CMI, particularly the discovery of the lymphocytes rather than bone marrow derived cells to elicit CMI.4 In the late 1960s and early 1970s, the bone marrow cells had a resurgence as an exceedingly small number of glass adherent bone marrow derived cells were identified as important for antigen presentation,5,6 and allostimulation,7 including skin dendritic cells.8,9 This culminated in the 2011 Nobel Prize for the role of innate immune dendritic cells and Janeway's concept of the innate immune system regulating the acquired.10,11
During the 1960s and 1970s, Klein and Van Scott, who shared in the 1972 Lasker Award, used CMI via contact sensitizers, particularly dinitrochlorobenzene (DNCB), to treat cancer.12,13 This brought topical immunotherapy to another level, making the 1960s and 1970s an exciting time in cellular immunology and cancer immunotherapy. When DNCB was reported as mutagenic in the Ames assay, the scientific process of topical cancer therapy with haptens slowed.14 Subsequently, hapten topical immunomodulation was resurrected, especially for the autoimmune disorder alopecia areata, with Happle's discovery of diphenylcycloporpenone (DPCP).15 The mechanisms of hapten therapy of cancer and autoimmune disease likely involve different pathways of CMI. An improved understanding of the immunopathogenesis of contact sensitivity is required to better comprehend these potential therapeutic applications of contact sensitivity. Kaplan et al. have recently published an excellent review covering current knowledge of the mechanisms involved in innate allergic contact dermatitis.16 Our present review emphasizes the historical discovery of cell mediated immunity through contact sensitivity in both innate and adaptive immunity and the role of contact sensitizers as powerful topical immunomodulators for the treatment of warts, skin cancer, autoimmune disorders,17 and allergies.18

Toll-like Receptors

Toll-like receptors (TLRs) are a subset of pattern recognition transmembrane receptors that are expressed on antigen presenting cells (APCs), whose stimulation causes activation innate immunity and ultimately adaptive immunity.19 Beutler explored TLR response to lipopolysaccharide involvement in innate immunity vis-à-vis infectious disease.20 The TLR role in contact sensitivity has also been probed and substantial results have surfaced. Askenase et al. found that mice treated with lipopolysaccharide (LPS) and the hapten, trinitrophenyl chloride (TNP-Cl), elicited a B-1 cell IgM response via invariant natural killer T (iNKT) cells. This response was absent when TLR4 and its adapter protein MyD88 were absent. They also found that TLR4 were present on iNKT cells and necessary to observe interleukin-4 (IL-4) production, a measure of immune response. They found the same response when Lipid A, a different TLR4 agonist, was applied. The immune effect of TLR2 agonists peptidoglycan and zymosan and TLR9 agonist CpG was also observed while dsDNA, agonist of TLR3, elicited no response.21