Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice

Rebecca Banerjee, R Lee Mosley, Ashley D. Reynolds, Alok Dhar, Vernice Jackson-Lewis, Paul H. Gordon, Serge Przedborski, Howard Eliot Gendelman

Research output: Contribution to journalArticle

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Abstract

Background: Innate neuroimmune dysfunction is a pathobiological feature of amyotrophic lateral sclerosis (ALS). However, links, if any, between disease and adaptive immunity are poorly understood. Thus, the role of T cell immunity in disease was investigated in human G93A superoxide dismutase 1 (SOD1) transgenic (Tg) mice and subsequently in ALS patients. Methods and Findings: Quantitative and qualitative immune deficits in lymphoid cell and T cell function were seen in G93A-SOD1 Tg mice. Spleens of Tg animals showed reductions in size, weight, lymphocyte numbers, and morphological deficits at terminal stages of disease compared to their wild-type (Wt) littermates. Spleen sizes and weights of pre-symptomatic Tg mice were unchanged, but deficits were readily seen in T cell proliferation coincident with increased annexin-V associated apoptosis and necrosis of lymphocytes. These lymphoid deficits paralleled failure of Copolymer-1 (COP-l) immunization to affect longevity. In addition, among CD4+ T cells in ALS patients, levels of CD45RA+ (naïve) T cells were diminished, while CD45RO+ (memory) T cells were increased compared to age-matched caregivers. In attempts to correct mutant SOD1 associated immune deficits, we reconstituted SOD1 Tg mice with unfractionated naïve lymphocytes or anti-CD3 activated CD4+CD25+ T regulatory cells (Treg) or CD4+CD25- T effector cells (Teff) from Wt donor mice. While naive lymphocytes failed to enhance survival, both polyclonal-activated Treg and Teff subsets delayed loss of motor function and extended survival; however, only Treg delayed neurological symptom onset, whereas Teff increased latency between disease onset and entry into late stage. Conclusions: A profound and progressive immunodeficiency is operative in G93A-SOD1 mice and is linked to T cell dysfunction and the failure to elicit COP-1 neuroprotective immune responses. In preliminary studies T cell deficits were also observed in human ALS. These findings, taken together, suggest caution in ascribing vaccination outcomes when these animal models of human ALS are used for study. Nonetheless, the abilities to improve neurological function and life expectancy in G93A-SOD1 Tg mice by reconstitution with activated T cells do provide opportunities for therapeutic intervention.

Original languageEnglish (US)
Article numbere2740
JournalPloS one
Volume3
Issue number7
DOIs
StatePublished - Jul 23 2008

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T-cells
Amyotrophic Lateral Sclerosis
Superoxide Dismutase
superoxide dismutase
T-lymphocytes
T-Lymphocytes
mice
Lymphocytes
Transgenic Mice
genetically modified organisms
Regulatory T-Lymphocytes
cells
lymphocytes
spleen
Animals
Spleen
Coat Protein Complex I
animal technicians
Immunization
Superoxide Dismutase-1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. / Banerjee, Rebecca; Mosley, R Lee; Reynolds, Ashley D.; Dhar, Alok; Jackson-Lewis, Vernice; Gordon, Paul H.; Przedborski, Serge; Gendelman, Howard Eliot.

In: PloS one, Vol. 3, No. 7, e2740, 23.07.2008.

Research output: Contribution to journalArticle

Banerjee, R, Mosley, RL, Reynolds, AD, Dhar, A, Jackson-Lewis, V, Gordon, PH, Przedborski, S & Gendelman, HE 2008, 'Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice', PloS one, vol. 3, no. 7, e2740. https://doi.org/10.1371/journal.pone.0002740
Banerjee R, Mosley RL, Reynolds AD, Dhar A, Jackson-Lewis V, Gordon PH et al. Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PloS one. 2008 Jul 23;3(7). e2740. https://doi.org/10.1371/journal.pone.0002740
Banerjee, Rebecca ; Mosley, R Lee ; Reynolds, Ashley D. ; Dhar, Alok ; Jackson-Lewis, Vernice ; Gordon, Paul H. ; Przedborski, Serge ; Gendelman, Howard Eliot. / Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. In: PloS one. 2008 ; Vol. 3, No. 7.
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abstract = "Background: Innate neuroimmune dysfunction is a pathobiological feature of amyotrophic lateral sclerosis (ALS). However, links, if any, between disease and adaptive immunity are poorly understood. Thus, the role of T cell immunity in disease was investigated in human G93A superoxide dismutase 1 (SOD1) transgenic (Tg) mice and subsequently in ALS patients. Methods and Findings: Quantitative and qualitative immune deficits in lymphoid cell and T cell function were seen in G93A-SOD1 Tg mice. Spleens of Tg animals showed reductions in size, weight, lymphocyte numbers, and morphological deficits at terminal stages of disease compared to their wild-type (Wt) littermates. Spleen sizes and weights of pre-symptomatic Tg mice were unchanged, but deficits were readily seen in T cell proliferation coincident with increased annexin-V associated apoptosis and necrosis of lymphocytes. These lymphoid deficits paralleled failure of Copolymer-1 (COP-l) immunization to affect longevity. In addition, among CD4+ T cells in ALS patients, levels of CD45RA+ (na{\"i}ve) T cells were diminished, while CD45RO+ (memory) T cells were increased compared to age-matched caregivers. In attempts to correct mutant SOD1 associated immune deficits, we reconstituted SOD1 Tg mice with unfractionated na{\"i}ve lymphocytes or anti-CD3 activated CD4+CD25+ T regulatory cells (Treg) or CD4+CD25- T effector cells (Teff) from Wt donor mice. While naive lymphocytes failed to enhance survival, both polyclonal-activated Treg and Teff subsets delayed loss of motor function and extended survival; however, only Treg delayed neurological symptom onset, whereas Teff increased latency between disease onset and entry into late stage. Conclusions: A profound and progressive immunodeficiency is operative in G93A-SOD1 mice and is linked to T cell dysfunction and the failure to elicit COP-1 neuroprotective immune responses. In preliminary studies T cell deficits were also observed in human ALS. These findings, taken together, suggest caution in ascribing vaccination outcomes when these animal models of human ALS are used for study. Nonetheless, the abilities to improve neurological function and life expectancy in G93A-SOD1 Tg mice by reconstitution with activated T cells do provide opportunities for therapeutic intervention.",
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N2 - Background: Innate neuroimmune dysfunction is a pathobiological feature of amyotrophic lateral sclerosis (ALS). However, links, if any, between disease and adaptive immunity are poorly understood. Thus, the role of T cell immunity in disease was investigated in human G93A superoxide dismutase 1 (SOD1) transgenic (Tg) mice and subsequently in ALS patients. Methods and Findings: Quantitative and qualitative immune deficits in lymphoid cell and T cell function were seen in G93A-SOD1 Tg mice. Spleens of Tg animals showed reductions in size, weight, lymphocyte numbers, and morphological deficits at terminal stages of disease compared to their wild-type (Wt) littermates. Spleen sizes and weights of pre-symptomatic Tg mice were unchanged, but deficits were readily seen in T cell proliferation coincident with increased annexin-V associated apoptosis and necrosis of lymphocytes. These lymphoid deficits paralleled failure of Copolymer-1 (COP-l) immunization to affect longevity. In addition, among CD4+ T cells in ALS patients, levels of CD45RA+ (naïve) T cells were diminished, while CD45RO+ (memory) T cells were increased compared to age-matched caregivers. In attempts to correct mutant SOD1 associated immune deficits, we reconstituted SOD1 Tg mice with unfractionated naïve lymphocytes or anti-CD3 activated CD4+CD25+ T regulatory cells (Treg) or CD4+CD25- T effector cells (Teff) from Wt donor mice. While naive lymphocytes failed to enhance survival, both polyclonal-activated Treg and Teff subsets delayed loss of motor function and extended survival; however, only Treg delayed neurological symptom onset, whereas Teff increased latency between disease onset and entry into late stage. Conclusions: A profound and progressive immunodeficiency is operative in G93A-SOD1 mice and is linked to T cell dysfunction and the failure to elicit COP-1 neuroprotective immune responses. In preliminary studies T cell deficits were also observed in human ALS. These findings, taken together, suggest caution in ascribing vaccination outcomes when these animal models of human ALS are used for study. Nonetheless, the abilities to improve neurological function and life expectancy in G93A-SOD1 Tg mice by reconstitution with activated T cells do provide opportunities for therapeutic intervention.

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