Immunological Properties of Glatiramer Acetate

Several immunological properties of GA are thought to contribute to the effects of GA.

8.14.4.1.1 Binding to major histocompatibility complex molecules

GA exhibits a very rapid, high, and efficient binding to many different MHC class II haplotypes on living murine and human antigen-presenting cells (APCs). GA was also shown to interact with purified human leukocyte antigen (HLA)-DR molecules - DR1, DR2, and DR4 - with high affinity.45 As a result of its high and efficient binding to MHC class II molecules, GA is capable of competing for binding with MBP and their myelin associated proteins, such as PLP and MOG, and even displace them from the MHC binding site.

8.14.4.1.2 Inhibition of T-cell responses by glatiramer acetate

It has been demonstrated that GA can competitively inhibit the immune response to MBP of diverse MBP-specific murine and human T-cell lines (TCLs) and clones, which have different MHC restrictions and respond to different epitopes of MBP.46-48 GA also inhibited the response of TCLs reactive with PLP and MOG peptides. These results suggest that the observed inhibition was due to competition between GA and nominal antigen for the MHC peptide-binding site. This mechanism may be less specific, and indeed GA was shown also to inhibit in vitro some other immune responses.48,49 In addition to the relatively nonspecific MHC-blocking, GA was shown to inhibit the response to the immunodominant epitope of MBP peptide 82-100 in a strictly antigen-specific manner by acting as T-cell receptor (TCR) antagonist.50

8.14.4.1.3 Induction of antigen-specific T-regulatory cells

In vivo studies have demonstrated that GA-treated animals (either by subcutaneous injections or by oral administration) develop GA-specific T suppressor (Ts) cells in the peripheral immune system. These cells can adoptively transfer protection against EAE.15,51 Furthermore, Ts cell hybridomas and lines that inhibited EAE in vivo could be isolated from spleen cells of mice rendered unresponsive to EAE by GA.52 These Ts cells were characterized as Th2/3-type cells secreting anti-inflammatory cytokines such as interleukin (IL)-4, IL10, and transforming growth factor (TGFb), but not Th1 cytokines, in response to both GAand MBP. Other myelin antigens such as PLP, MOG and ab crystalline could not activate the GATs cells to secrete Th2 cytokines. Yet the disease induced by PLP and MOG can be suppressed by these Ts cells, probably due to a bystander suppression mechanism.53,54 More recently, it has been demonstrated that these GA-specific Th2 suppressor T cells which were induced in the periphery by either injection or oral treatment accumulate in the brain.55,56

The GA-specific cells accumulated in the CNS demonstrated in situ extensive expression of the anti-inflammatory cytokines IL10 and TGFband the brain-derived neurotrophic factor (BDNF), but not the inflammatory cytokine IFN-g. Furthermore, the GA-induced cells infiltrating the brain induced bystander expression of IL10 and TGFb by resident astrocytes and microglia.57 These findings clearly indicate that the GA-specific cells which penetrate the CNS function in vivo as regulatory cells and mediate the therapeutic effect of GA in the target organ.

It was recently suggested that, in addition to the induction of GA-specific Th2 cells, GA also led to the conversion of CD4 + CD25- T cells to CD4 + CD25 + regulatory T cells through activation of transcription factor Foxp3.58 The induction of Foxp3 by GA was mediated through its ability to produce IFN-g and, to a lesser extent, TGFb These findings were demonstrated both in MS patients treated with GA and in wild-type B6 mice, but not in IFN-g knockout mice.

8.14.4.1.4 Effect of glatiramer acetate on antigen-presenting cells

Several groups have recently reported on the effects of GA on various types of APC. Thus GA blocked lipopolysaccharide-mediated induction of several activation markers of human monocytes and the release of tumor necrosis factor (TNF-a) and IL12. On the other hand, it induced increased production of IL10 by the monocytes.59,60 Similarly, GA inhibited production of IL2 and TNF-a by in vitro-generated human dendritic cells (DC). DC exposed to GA induced IL4-secreting Th2 cells and enhanced the level of IL10.61 There is also evidence that GA treatment modifies in vivo the properties of APC. Thus, the spontaneous and triggered release of IL10 was enhanced in monocytes from GA-treated patients whereas the stimulated secretion of IL12 was reduced.60 It is not clear, however, whether in vivo GA affects the monocytes directly or indirectly by TH2 cytokines secreted by GA-specific T cells. It seems that APC deviation into APC favoring Th2 differentiation may be an additional contributing factor to the therapeutic effect of GA.

8.14.4.1.5 Neuroprotective effects of glatiramer acetate

Recent studies have revealed an additional aspect of GA activity - neuroprotective effects that might also be relevant to MS. It was demonstrated that, similarly to MBP, active immunization with GA as well as adoptive transfer of Tcells reactive to GA can inhibit the progression of secondary degeneration after crush injury of the rat optic nerve.62 The GA-specific T cells secreted significant amounts of BDNF,62 a neurotrophin that plays a major role in neuronal survival. Furthermore, vaccination with GA protected neurons against glutamate cytotoxicity,63 and aggregated beta-amyloid-induced toxicity.64

GA treatment also increased survival time and improved motor function in a mouse model of amyotrophic lateral sclerosis.65 Adoptive transfer of GA-specific Tcells was effective in protecting dopaminergic neurons in a mouse model of Parkinson disease.66 Taken together, these results show that GA may have neuroprotective functions in human neurodegenerative diseases.

Several lines of evidence suggest that GA also has a neuroprotective effect in EAE and MS. The effect of GA was studied in MOG-induced EAE, which is considered to be a model that simulates neurodegeneration more than inflammation.67 It was demonstrated that GA immunization attenuates both inflammation and associated neuronal axonal damage. In the murine model of Theiler's virus-induced demyelinating disease, it was demonstrated that polyreactive antibodies to GA promoted myelin repair.68

As indicated before, we have demonstrated that adoptively transferred GA reactive cells migrate to the CNS and also produce in situ BDNF in addition to anti-inflammatory cytokines.57 In this regard it should be noted that the BDNF receptor trkB is expressed in neurons and astrocytes in MS lesions.69 Therefore, BDNF secreted by GA-specific cells in the CNS could exert neurotrophic effects directly in the MS target tissue.

Human GA-specific T cells, of both TH1 and Th2 type, are capable of producing BDNF. Studying BDNF production by 73 GA and 33 MBP reactive short-term TCLs, it was found that the mean BDNF level for the GA cell lines was significantly higher than that for MBP lines.71

There are also limited clinical data pointing to the neuroprotective effects of GA therapy. Thus, in the European Canadian MRI study, it was demonstrated that GA produced a 50% reduction in the proportion of new MS lesions evolving into persistent black holes72 (i.e., lesions where severe tissue disruption has occurred). In another study, N-acetylaspartate (NAA), which is a reliable marker of neuronal and axonal injury, was measured using magnetic resonance spectroscopy.73 In patients treated with GA for 2 years, the ratio of NAA to creatinine increased from 1.96 at baseline to 2.17, while it declined from 2.01 to 1.83 in untreated patients. These results, as well as the results described earlier on the effect of GA on brain atrophy,40 indicate that GA affects positively three different MRI surrogate markers of neuroprotection (black holes, NAA level, and brain atrophy).

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