CD40L in autoimmunity and mucosally induced tolerance
Authors: Mi-Na Kweon, Hiroshi Kiyono
Journal: Journal of Clinical Investigation (2002)

The administration of soluble antigens to the oral or nasal mucosa can lead to systemic unresponsiveness to a subsequent challenge with the same antigens (1). Such mucosally induced tolerance probably protects the body from hypersensitivity reactions to food proteins, pollen, and commensal bacterial antigens present in the normal mucosa and thus helps maintain an appropriate immunological balance between the host and its normal flora. Numerous molecular and cellular inhibitory mechanisms are involved in this unique and important immunological phenomenon. Several lines of evidence show that mucosally induced tolerance does not occur passively, by means of anergy, clonal deletion, or the simple absence of autoreactive immune cells, but also involves ignorance, receptor downregulation, or active cellular suppression (ref. 2; Figure ​Figure11a).



Figure 1

Models for the effects on mucosally induced tolerance of perturbing the CD40L-CD40 interaction. (a) In the untreated wild-type mouse, CD40 on dendritic cells (DCs) and other APCs interacts with CD40L expressed on T cells of several subsets, including ...



The fact that mucosally induced tolerance can suppress antigen-specific T cell proliferation, delayed-type hypersensitivity responses, and antibody production suggests attractive ap-proaches for the prevention and control of autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, encephalomyelitis, and type 1 diabetes (3). However, although mucosal administration of different autoantigens has been tested in human trials, this strategy has not yet yielded a successful therapy (4, 5). Some previous studies have suggested that this failure of human trials was due to concomitant induction of harmful cytotoxic T lymphocytes (CTLs) by mucosally administered antigen (6, 7).

In an attempt to overcome this obstacle, as reported in this issue of the JCI, Hanninen et al. (8) have induced a temporary blockade of the interaction between the costimulatory protein CD40 and its ligand CD40L. This interaction has been suggested to foster mucosally induced tolerance by several mechanisms, as shown in Figure ​Figure1a.1a. In their present report, the authors show that blocking antibodies to CD40L can prevent the development of antigen-specific CTL responses without affecting the development of oral tolerance.

Hanninen and colleagues (8) tested this approach in rat insulin promotor-OVA (RIP-OVA) mice, a diabetic transgenic strain in which the expression of the model antigen chicken ovalbumin (OVA) in the pancreatic β-islet cells provokes an autoimmune response to these cells. The consequent destruction of these islet cells thus provides a model for the events seen in type I diabetes. Oral administration of a high dose of OVA can promote mucosally induced tolerance, but this treatment also elicits CTL specific for OVA. However, Hanninen et al. observed that transient blockade of CD40L in this system prevented CTL responses without affecting mucosally induced tolerance toward OVA, either in wild-type or in RIP-OVA transgenic mice (Figure ​(Figure1b).1b). Furthermore, the severity of diabetes, as measured, for example, by blood glucose, was significantly improved after transient blockade of CD40L, suggesting that modulation of CD40L-CD40 interaction could be used clinically to uncouple the desired systemic, autoantigen-specific unresponsiveness from the oral induction of CTLs.