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Review
, 2014, 175265

Hapten-induced Contact Hypersensitivity, Autoimmune Reactions, and Tumor Regression: Plausibility of Mediating Antitumor Immunity

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Review

Hapten-induced Contact Hypersensitivity, Autoimmune Reactions, and Tumor Regression: Plausibility of Mediating Antitumor Immunity

Dan A Erkes et al. J Immunol Res.

Abstract

Haptens are small molecule irritants that bind to proteins and elicit an immune response. Haptens have been commonly used to study allergic contact dermatitis (ACD) using animal contact hypersensitivity (CHS) models. However, extensive research into contact hypersensitivity has offered a confusing and intriguing mechanism of allergic reactions occurring in the skin. The abilities of haptens to induce such reactions have been frequently utilized to study the mechanisms of inflammatory bowel disease (IBD) to induce autoimmune-like responses such as autoimmune hemolytic anemia and to elicit viral wart and tumor regression. Hapten-induced tumor regression has been studied since the mid-1900s and relies on four major concepts: (1) ex vivo haptenation, (2) in situ haptenation, (3) epifocal hapten application, and (4) antigen-hapten conjugate injection. Each of these approaches elicits unique responses in mice and humans. The present review attempts to provide a critical appraisal of the hapten-mediated tumor treatments and offers insights for future development of the field.

Figures

Figure 1
Figure 1
The likely pathway of the “sensitization” phase of contact hypersensitivity. (a) Hapten application induces strong innate immune mechanisms, causing cell death and the release of danger signals and endogenous ligands, leading to cytokine release, IL-1β, IL-18, TNFα, and GM-CSF, by keratinocytes (KC). This release will stimulate dermal antigen-presenting cells (dAPCs), langerhans cells, and dermal dendritic cells, to take up haptenated antigen and migrate to the dLN to activate naïve T-cells. Mast cells will aid in this migration by releasing TNFα. (b) iNKT cells in the liver will be activated by APCs presenting haptenated glycolipid by CD1d. This will cause cytokine release, IL-4, to stimulate naïve B-1 cells in the peritoneal cavity, along with the binding of hapten-antigen by membrane IgM. This will cause migration of these cells to the dLN, and subsequent maturation into CS-initiating B-1 cells, which release antihapten IgM into circulation.
Figure 2
Figure 2
The likely pathway of the “early elicitation” phase of contact hypersensitivity. The red arrows and type indicate the early elicitation phase. Hapten challenge will restimulate iNKT cells to release IL-4, which along with hapten-antigen will stimulate CS-initiating B-1 cells as seen in Figure 1. These cells will release IgM, which will bind to hapten-antigen. This will cause formation of C5a, triggering activation of mast cells to produce TNFα and serotonin, increasing immune cell trafficking into the area and TNFα and CXCL2 to stimulate neutrophils in the dermis. Neutrophils will also be activated by CXCL1 and CXCL2 released from haptenation of the keratinocytes. Their activation will cause damage at the challenge site as well as more CXCL1 and CXCL2 release, inducing immune cell trafficking to the area as illustrated in Figure 3. Lastly, haptenated keratinocytes will release cytokines to induce immune cell trafficking to the area as depicted in Figure 3.
Figure 3
Figure 3
The likely pathway of the “late elicitation” phase of contact hypersensitivity. The red type indicates the “early” elicitation phase and the black arrows indicate the “late” elicitation phase. Hapten-specific memory T-cells will traffic to the hapten challenge site, where they will enter the dermis and divide into multiple different cells subsets. This will be initiated by dermal APCs presenting antigen as well as cytokine release from multiple different cell subsets. The multiple subsets will play different roles in the CHS reaction at the site. Lastly, CXCR6+ hepatic NK cells will traffic to the hapten challenge site and elicit damage.

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