Adaptive Immune Neuroprotection in G93A-SOD1 Amyotrophic Lateral Sclerosis Mice

• Published in: PloS one Vol. 3; no. 7; p. e2740
• Main Authors: Banerjee, Rebecca, Mosley, R. Lee, Reynolds, Ashley D., Dhar, Alok, Jackson-Lewis, Vernice, Gordon, Paul H., Przedborski, Serge, Gendelman, Howard E.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.07.2008; Public Library of Science (PLoS)
• Subjects: Adaptive immunity; Alzheimer's disease; Alzheimers disease; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - immunology; Animal models; Animals; Apoptosis; B cells; Biology; CD25 antigen; CD3 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; CD45RA antigen; Cell proliferation; Cell survival; Comparative analysis; Copolymers; Dementia; Effector cells; Genetic engineering; Homeostasis; Human subjects; Humans; Immune response; Immune System; Immunity; Immunization; Immunodeficiency; Immunological memory; Immunology; Immunology/Immune Response; Immunoregulation; Interleukin-2 Receptor alpha Subunit - biosynthesis; Latency; Life expectancy; Life span; Longevity; Lymphocytes; Lymphocytes - cytology; Lymphocytes T; Medical research; Memory cells; Metabolism; Mice; Mice, Transgenic; Necrosis; Neurodegeneration; Neurological Disorders/Movement Disorders; Neurology; Neuroscience; Neuroscience/Motor Systems; Neuroscience/Neurobiology of Disease and Regeneration; Neurosciences; Patients; Pharmacology; Phenotype; Rodents; Spleen; Spleen - metabolism; Superoxide dismutase; Superoxide Dismutase - genetics; Superoxides; Survival; T cells; T-Lymphocytes - immunology; Transgenic mice; Vaccination; Vaccines; Weight reduction; New York; United States > US; Nebraska
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0002740

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. 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-1) 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. 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.