Immunology and Possible Mechanisms of Action

Although substantial research has been undertaken into potential mechanisms of action of thalidomide, there are no definitive conclusions to explain its clinical efficacy. Indeed, as groups delve further into the effects of thalidomide, more and more putative mechanisms have been reported. Identifying which of these mechanisms are relevant, particularly with respect to its effects in different diseases, has proven diffi cult to dissect. Thalidomide has many metabolites, some of which may contribute to its biological activity. Here, we confine discussion to the actions of thalidomide itself. Thalidomide interferes with both innate and adaptive and cellular and molecular components of immunity.

Much work has focused on the effects of thalidomide on tumor necrosis factor (TNF)-a, a proinflammatory cytokine involved in host defense and identified as important in several infectious, inflammatory, and autoimmune diseases. In vitro studies show that thalidomide selectively and partially inhibits human monocyte synthesis of TNF-a, possibly via an increased rate of degradation of TNF-a messenger RNA (mRNA), with a reduction in half-life of TNF-a mRNA from 30min to 17min (Sampaio et al. 1991, Moreira et al. 1993, Corral and Kaplan 1999). Thalidomide may inhibit activation of NF-kB, a transcription factor that affects TNF-a and TNF-p genes (Keifer et al. 2001,Walchner et al. 1995).

This correlates with in vivo data from patients with erythema nodosum leprosum, a condition characterized by overproduction of TNF-a. Clinical improvement with thalidomide was accompanied by a corresponding decrease in serum TNF-a levels (Sampaio et al. 1991). In tuberculosis, regardless of whether there was associated HIV infection, plasma TNF-a and monocyte TNF-a mRNA levels fell on thalidomide treatment, in parallel with accelerated weight gain (Tramontana et al. 1995). In contrast, increased serum TNF-a levels were observed in thalidomide-treated HIV-asso-ciated oral ulceration (Jacobson et al. 1997) and in toxic epidermal necrolysis (Wolkenstein 1998).

It is clear, therefore, that in considering the relationship between thalidomide and TNF-a, attention must be paid to the difference between in vitro and in vivo scenarios, the pathophysiology of different diseases, and technical considerations of TNF-a measurement. Measurement of serum levels of TNF-a may not necessarily reflect TNF-a activity, as this may detect receptor-bound circulating homotrimer, which may be inactive. Technical difficulties, such as an undefined normal range, a short half-life, and phasic release of TNF-a, may also confound accurate measurement (Calabrese and Fleischer 2000).

TNF-a is elevated in active SLE, but the ratio of TNF-a to the soluble TNF-a receptor (TNF-sR) is lower in SLE than in rheumatoid arthritis. It has been suggested that the ratio of TNF-a to TNF-sR may be more critical than the absolute level of serum TNF-a. Indeed, there may be a relative deficiency of active TNF-a in SLE (Dean et al. 2000). Lee et al. reported an increased risk of nephritis in patients with low peripheral blood mononuclear cell TNF-a levels (Lee et al. 1997). TNF-a levels may relate to HLA haplotype. HLA-DR2, DQw1-positive patients with SLE have low levels of TNF-a inducibility and an increased incidence of lupus nephritis, whereas the DR4 haplotype, associated with high inducibility of TNF-a, has a negative relationship with lupus nephritis (Jacob et al. 1990). Although serum levels of TNF-a are important, local tissue expression of TNF-a may also be relevant to specific organ involvement. For example, Herrera-Esparza et al. reported glomerular and tubular deposition of TNF-a in 52% of renal biopsy samples from 19 patients with lupus nephritis (Herrera-Esparza et al. 1998).

In conclusion, the discovery of the in vitro effects of thalidomide on TNF-a in vitro does not allow direct extrapolation to clinical lupus, in which more complex interactions are likely to exist.

Thalidomide has multiple effects on T lymphocytes, which may have an important pathogenic role in lupus. Histopathologic examination in SLE and DLE typically reveals the presence of a lymphocytic infiltrate, predominantly T cell in nature, characterized by CD3 expression. These cells are typically activated, and the relative proportions of CD4 and CD8 may vary between SLE and DLE (Kohchiyama et al. 1985)

Thalidomide affected the ratio of peripheral blood T-helper (Th) to T-suppressor cells in healthy male volunteers, with a fall in Th cells and an apparent increase in T-suppressor cells (Gad et al. 1985). Thalidomide has been shown to affect Th1/Th2 cytokines in vitro. It inhibits production of the Th1 cytokine interferon (IFN)-y and enhances production of the Th2 cytokines interleukin (IL)-4 and IL-5 in peripheral blood mononuclear cell cultures though effects vary with culture time (McHugh et al. 1995). It also inhibits monocyte production of the Th1 cytokine IL-12 in a dose-dependent manner.

Thalidomide has been shown in vitro to co-stimulate human T cells that have received signal 1 through the T-cell receptor complex, with resultant increased IL-2-mediated T-cell proliferation and IFN-y production (Haslett et al. 1998). CD8+ lymphocytes show a more marked co-stimulation than CD4+ lymphocytes. In this setting, it is noteworthy that TNF-a production by anti-CD3-stimulated T cells was not inhibited by thalidomide, in contrast to its effects on monocytes. Thus, the effect of thalidomide may depend on the cell type and also on the nature of the stimulus. Despite its immunomodulatory effects, thalidomide does not seem to predispose to risk of significant infections, which maybe related to its co-stimulatory effects on T cells.

Thalidomide also has effects on the humoral system, which of course is abnormal in SLE, characterized by hypergammaglobulinemia, and autoantibody production to multiple nuclear and cellular antigens. IgM levels fell in patients with erythema nodosum leprosum treated with thalidomide. Mice fed thalidomide for 5-7 days before immunization with sheep red blood cells exhibited lower IgM production (Shannon et al. 1981). In a series of patients with SLE and cutaneous features treated with thalidomide, the gammaglobulin level fell significantly in 10 of 13 patients (Atra and Sato 1993).

Innate immune mechanisms such as neutrophil and monocyte function are affected by thalidomide. For example, thalidomide inhibits neutrophil chemotaxis and phagocytosis and monocyte phagocytosis (Barnhill et al. 1984, Faure et al. 1980), which may be important in inflammatory diseases, including cutaneous forms of LE. Effects on phagocytes may relate to down-regulation of cell adhesion molecules.Vas-cular adhesion molecule expression has been noted in lesional, nonlesional, and non-sun-exposed skin in SLE (Belmont et al. 1994, Jones et al. 1996). Thalidomide may affect the density of TNF-a-induced intercellular adhesion molecule-1, vascular adhesion molecule-1, and E-selectin antigens in human endothelial cell cultures (Geitz et al. 1996, Settles et al. 2001).

Thalidomide has been shown to have antiangiogenic effects in vitro and in vivo. Endothelial cell proliferation in vitro has been shown to be inhibited by thalidomide (Moreira et al. 1999). Several growth factors are implicated in the development of human tumors, including basic fibroblast growth factor. The antiangiogenic properties of thalidomide may occur via inhibition of basic fibroblast growth factor-induced angiogenesis, as shown in vivo in a rabbit cornea micropocket assay (D'Amato et al.

1994). Thalidomide also has effects on other growth factors, for example, it is effective in inhibition of corneal angiogenesis induced by vascular endothelial growth factor (Kruse et al. 1998).

The antiangiogenic effects of thalidomide may correlate with its efficacy in malignant disease and with its teratogenicity, although not with TNF-a inhibition. It has been suggested that the effects of thalidomide on TNF-a and T cells may be more pertinent to its effect on immune and inflammatory disease, whereas antiangiogenic effects may have more impact on malignant disease; however, it seems likely that there is some degree of crossover in these effects.

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