Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2000 Apr;105(7):967-76.
doi: 10.1172/JCI8970.

Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis

P W Duda  1 , M C Schmied, S L Cook, J I Krieger, D A Hafler
Affiliations
Clinical Trial

Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis

P W Duda et al. J Clin Invest. 2000 Apr.

Abstract

We examined the effect of glatiramer acetate, a random copolymer of alanine, lysine, glutamic acid, and tyrosine, on antigen-specific T-cell responses in patients with multiple sclerosis (MS). Glatiramer acetate (Copaxone) functioned as a universal antigen, inducing proliferation, independent of any prior exposure to the polymer, in T-cell lines prepared from MS or healthy subjects. However, for most patients, daily injections of glatiramer acetate abolished this T-cell response and promoted the secretion of IL-5 and IL-13, which are characteristic of Th2 cells. The surviving glatiramer acetate-reactive T cells exhibited a greater degree of degeneracy as measured by cross-reactive responses to combinatorial peptide libraries. Thus, it appears that, in some individuals, in vivo administration of glatiramer acetate induces highly cross-reactive T cells that secrete Th2 cytokines. To our knowledge, glatiramer acetate is the first agent that suppresses human autoimmune disease and alters immune function by engaging the T-cell receptor. This compound may be useful in a variety of autoimmune disorders in which immune deviation to a Th2 type of response is desirable.

PubMed Disclaimer

Figures

Figure 1
Figure 1
The proliferative response to GA is decreased on average after daily injections of GA. The antigen-specific proliferative response of 20 or 30 primary T-cell lines induced with 40 μg/mL GA as described in Methods was measured by split-well assay for each patient at each time point. Before and at 6 months of treatment, all 7 patients could be tested; at 3 and 12 months, data for 5 patients were obtained. (a) Each panel represents data from an individual patient. Squares represent mean ± SEM proliferation in Δ cpm of the GA-specific response compared with the no-antigen control. Background levels of the [3H]thymidine incorporation for all patients of the no-antigen condition were 1,747 ± 111 before treatment, and 3,286 ± 175, 3,785 ± 262, and 3,509 ± 239 at 3, 6, and 12 months of treatment, respectively. The numbers in the figure indicate the SI over the no-antigen control for each time point. (b) The mean stimulation index SI ± SEM for all T-cell lines from all patients tested at each time point is shown.
Figure 2
Figure 2
GA-specific secretion of cytokines is polarized toward a Th2 response after daily injections of GA. The GA-specific secretion of the cytokines IL-5 and IFN-γ was measured in T-cell lines by 2 methods: ELISPOT (a) and ELISA (b) assays. Each symbol represents the difference of spots counted or Δ pg/mL measured in split-well assays between the GA (20 μg/mL) condition and the no-antigen control. The limits of detection were 1 spot and 10 pg/mL, respectively. Numbers represent the percentage of T-cell lines in each quadrant with a minimum difference in spots of twice the SD of the negative controls for IL-5 and IFN-γ, respectively.
Figure 3
Figure 3
IL-13 secretion is increased after daily injections of GA. Primary T-cell lines were set up in 10 identical wells each in the presence of no antigen or with 1.0, 10, and 100 μg/mL GA and cultured as described in Methods. Identical wells were pooled on day 11, and 30,000 T cells each were restimulated with no antigen or 1.0, 10, and 100 μg/mL GA pulsed on 100,000 autologous APCs. Cytokines were measured in supernatants by ELISA after 48 hours as described, and proliferation was measured by [3H]thymidine incorporation. Asterisks point at values that were above the upper limit of detection of the IL-13 assay of 10,000 pg/mL.
Figure 4
Figure 4
Cross-reactivity of GA-reactive T-cell lines is increased after daily injections of GA. Percentages of the GA-induced T-cell lines cross-reacting to each APL tested at each time point are shown for the 7 patients encoded by gray scale. Proliferative IFN-γ and IL-5 responses were examined for all T-cell lines and are represented separately in the top, middle, and lower third. A minimum SI of 2 and a difference of 2 SD over the background was required for classification as a cross-reactive T-cell line.
Figure 5
Figure 5
(a). The proliferative response to MBP 84-102 is not altered after daily injections of GA. A total of 900 T-cell lines were generated in response to MBP 84-102. The proliferative response in Δ cpm is given for each of 30 or 40 lines tested at each time point (circles, Δ cpm on left axes). On the right axes, the percentage of positive lines determined by a minimum 2.5-fold increase over background and a minimum difference of 1,500 cpm is shown (line). The mean background was 4,662 ± 138. (b). No changes occur in the cytokine response to MBP 84-102 after daily injections of GA. Lines having a minimum difference to the negative control of 2 SD, i.e., 70 spots for IFN-γ and 19 spots for IL-5, were considered positive for the respective cytokine.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Hafler DA. The distinction blurs between an autoimmune versus microbial hypothesis in multiple sclerosis. J Clin Invest. 1999;104:527–529. - PMC - PubMed
    1. Windhagen A, et al. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. J Exp Med. 1995;182:1985–1996. - PMC - PubMed
    1. Grewal IS, et al. Requirement for CD40 ligand in costimulation induction, T cell activation, and experimental allergic encephalomyelitis. Science. 1996;273:1864–1867. - PubMed
    1. Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992;358:155–157. - PubMed
    1. Windhagen A, et al. Cytokine secretion of myelin basic protein reactive T cells in patients with multiple sclerosis. J Neuroimmunol. 1998;91:1–9. - PubMed

Publication types

MeSH terms