Downregulation of the Immune Response

DOWNREGULATION OF THE IMMUNE RESPONSE

Many different mechanisms are involved in the downregulation of the immune response. Extreme situations of downregulation may very well be indistinguishable from tolerance. This similarity between activation of suppressor circuits and clonal anergy is made more obvious by the fact that the experimental protocols used to induce one or the other are vir-tually identical. However, there are defined mechanisms that result in the downregulation of the immune response through the activation of a variety of immunoregulatory cells that, under the right circumstances, downregulate the immune response. Both monocytes and T lymphocytes appear able to have downregulatory properties. Monocyte-mediated suppres-sion is usually due to the release of PGE2 and is nonspecific. The situation with lympho-cytes is more complex, involving more than one type of cell.

A. Suppressor T Cells

For a couple of decades there was intense research on a CD8+ suppressor T-cell subpopu-lation. In mice, those cells mediated antigen-specific suppression via suppressor factors that may simply represent released TcR molecules. However, attempts to isolate and se-quence suppressor factors or to clone their genes have met with failure. It has also been im-possible to clone T-suppressor cells, so their existence as a defined subpopulation has not been confirmed.

In humans there is some evidence suggesting that immunoregulatory CD8+ lympho-cytes, after antigen-specific stimulation, may exert their effect by releasing nonspecific suppressor factors such as TGF-βand interleukin-10. Since the trigger for the release of these factors would be the specific recognition of an antigen, and the effects of soluble fac-tors must be limited to cells in the immediate vicinity of the stimulated cell, the suppres-sion would predominantly affect helper T cells recognizing the same antigen in association with an MHC-II molecule.

B. Mucosal Tolerance

Recent reports of therapeutic benefit of oral administration of collagen to patients with rheumatoid arthritis raised considerable interest in the concept of oral tolerance. This phe-nomenon had been first observed by H. G. Wells in 1911, when he demonstrated that guinea pigs sensitized to hen albumin (ovalbumin) would develop systemic anaphylaxis af-ter reexposure to the antigen unless they were previously given the antigen with their food. The recent investigations have demonstrated that tolerance can also be induced by admin-istration of antigen (such as ovalbumin) by inhalation.

The sum of experimental data collected so far suggests that the administration of large doses of oral antigen causes TH1 anergy-driven tolerance. However, this seems to be a rather exceptional mechanism, with little clinical application. In contrast, the administra-tion of low doses of antigen is believed to stimulate TH2 responses and cause bystander sup-pression of autoreactive TH1 cells. A proposed framework for this type of suppression is as follows:

1.           The ingested antigen (usually a protein) is transported to submucosal accessory cells in the Peyer’s patches, where it is processed and presented to regulatory T cells (both CD4+ and CD8+ phenotypes, including special subpopulations of γδCD4+ and CD8+ T cells), which after proliferation and differentiation become functionally suppressor. The suppressor effect is mediated by secretion of TGF-β, IL-10, and IL-4 after reexposure to the tolerizing antigen.

2.           When antigen is introduced in small doses as a nasal aerosol, the main effect seems to be the stimulation of immunoregulatory γδCD8+ cells that cause a shift from a predominant and pathogenic TH1 response to a less harmful TH 2 re-sponse.

3.           The activated regulatory T cells enter the circulation and are attracted to areas of ongoing reactivity. In the peripheral lymphoid tissues they may downregulate immune responses to the tolerizing antigen. In tissues where effector cells are causing inflammatory changes, the recruitment of activated regulatory T cells re-leasing TGF-β and IL-10 may suppress the activity of TH1 assisting the local im-mune response process, resulting in a downregulation of the inflammatory response.

The antigen used to induce oral tolerance does not need to be identical to that rec-ognized by the autoreactive T cells in vivo, since the suppressor effects of IL-10 and TGF-β are nonspecific and can affect T cells reacting with other antigens (bystander sup-pression). However, the best results with oral tolerization protocols are obtained when antigens structurally related to the autoantigens are given orally. Thus, cross-reactivity between the two antigens may be important in localizing the activated suppressor CD8+ cells to the right tissue.

C. Anti-idiotypic Immune Responses