The form of vitamin D3 that is active in the human body influences
various functions of the immune system such as the production of different mediators and the expression of surface molecules important for cellular interactions. On this basis, it has been used successfully to treat psoriasis, an autoimmune disease of the skin. Could vitamin D3 analogues also be used to treat type 1 diabetes, likewise an autoimmune disease? Animal experiments have yielded some very promising results.
An immunoregulatory nuclear receptor
The vitamin D receptor (VDR) is a nuclear receptor. The genetic information for the synthesis of this receptor is located on chromosome 12 (Fig. 2); it can show considerable polymorphism, i.e. difference between individuals. As reported by Pani and Chang, certain VDR gene polymorphisms are associated with type 1 diabetes (T1D) [6, 7]. Vitamin D receptors are activated when certain mediator substances, or ligands, dock at them. This ligand function can be exerted not only by vitamin D compounds, but also by steroid hormones, thyroid hormones and vitamin A1 acid. By binding to the receptor, these ligands regulate the metabolism of calcium and phosphate, and thus also of bone, and control cell replication and differentiation. This occurs via an influence on the synthesis of certain regulatory proteins. Nevertheless, VDRs are to be found not just in cells that play a role in calcium and bone metabolism, but also in cells of the immune system. Here they play an immunoregulatory role. When a VDR is activated by binding of a ligand, it exerts its action as a transcription factor. This means that it binds to specific sites on DNA (deoxyribonucleic acid), the molecule in the cell nucleus that bears genetic information, and thereby initiates the synthesis of certain regulatory proteins. The presence of VDRs in most cells of the immune system, especially in antigenpresenting cells (APCs) such as macrophages and dendritic cells (DCs) and in CD4+ and CD8+ T lymphocytes, led investigators to consider the potential use of 1,25(OH)2D3 as an immunomodulatory drug to influence immune reactions mediated by T lymphocytes (T cells). The immunoregulatory properties of 1,25 (OH)2D3 are now being exploited for clinical purposes including the treatment of psoriasis, a Th1-cell-mediated autoimmune disease of the skin .
A mouse model of diabetes
NOD (nonobese diabetic) mice are an ideal experimental model for the development of new approaches to the treatment of autoimmune diabetes, since their genetic predisposition to defective regulation of Th1 lymphocytes causes them to develop type 1 diabetes (T1D) spontaneously. The course of the disease resembles that of the human T1D. Many of the findings referred to below on interactions between protective and destructive cells in the development of autoimmune T1D have been obtained in the NOD mouse (Fig. 3). The key step in T1D is the activation of pathogenic T lymphocytes that can destroy the insulin-producing _ cells of the pancreas. These include CD8+ T lymphocytes and macrophages that are regulated by interleukin (IL)-12- dependent Th1 lymphocytes. After being activated by various stimuli of bacterial or viral origin, antigen-presenting cells, in particular dendritic cells and macrophages, produce a series of mediators (cytokines) such as IL-12 and IL-10 that exert opposing effects. If the formation of IL-12 predominates, relatively more Th1 lymphocytes are produced. In turn,
Th1 lymphocytes themselves increase the production of IL-12 by dendritic cells. The signal for this is given when the CD154 molecule present on the surface of Th1 lymphocytes binds to the receptor molecule CD40 present on the surface of dendritic cells. Th1 lymphocytes also produce large amounts of interferon-_ (IFN-_), which further stimulates IL-12-induced formation of Th1 lymphocytes. IFN-_ also induces macrophages to become cytotoxic and to release mediator substances that are toxic to the _ cells of the pancreas. In addition, IFN-_ and IL-2 stimulate cytotoxic CD8+ cells, which release other mediator substances that are toxic to _ cells. Th1 lymphocytes can also damage _ cells directly by releasing cytokines such as IFN-_. Destruction of the insulin-producing _ cells of the pancreas via these different effector mechanisms leads to the release of _ cell components such as proinsulin, GAD (glutamic acid decarboxylase) and IA-2 (tyrosine phosphatase-like molecule). Once released from _ cells, these
molecules act as antigens and are presented to T lymphocytes by antigen-presenting cells. Antibodies against components of the _ cells of the pancreas are produced, resulting in further destruction of these cells.
At the same time, regulatory mechanisms that could limit the pathogenic activity of Th1 lymphocytes, such as
❚ inhibition of IL-12 production by dendritic cells via release of the antagonist IL-10 by Th2 cells,
❚ downregulation of the Th1 cell population by direct contact between Th1 cells and CD4+CD25+ regulatory T cells and
❚ the action of regulatory substances produced by natural killer cells, are defective in the NOD mouse .
FIGURE 3: Schematic representation of cellular interactions in the development of type 1 diabetes. Figure adapted from . Source: L. Adorini, Bio-Xell, Milan, Italy.
How does 1,25(OH)2D3 modulate the immune response?
A number of mechanisms have been identified explaining how 1,25(OH)2D3, the form of vitamin D3 that is active in the body, and similar compounds can influence the immune response in secondary lymphoid organs and in tissues affected by autoimmune destructive processes (Fig. 4).
FIGURE 4: 1,25(OH)2D3 and its analogues can influence the immune response in secondary lymphoid tissues and in target tissues via a number of mechanisms. Broken lines indicate cytotoxicity, green arrows represent stimulation, blunted red arrows indicate inhibition. Figure adapted from . Source: L. Adorini, BioXell, Milan, Italy
Effect on Th1 cells in lymphoid organs
In secondary lymphoid organs these compounds inhibit the production of IL-12 and stimulate production of IL-10, which blocks the development of Th1 cells. In addition, 1,25(OH)2D3 and similar compounds exert a Th1 cell-inhibiting effect via
❚ downregulation of the costimulatory molecules (CD40, CD80, CD8) expressed by dendritic cells and
❚ induction of CD4+CD25+ regulatory T cells and Th2 cells. 1,25(OH)2D3 also exerts a direct effect on T cells in that it inhibits production of interleukin-2 and interferon-_. Interleukin- 2, which is produced by activated T cells, acts as a T cell growth factor that stimulates the proliferation of T cells. IL-2 also increases the production of antibody-forming B lymphocytes and has a stimulatory effect on cytotoxic macrophages and cytotoxic T lymphocytes.