ImmunoAblation Followed By Autologous Hematopoietic Stem Cell Infusion For The Treatment Of Severe AutoImmune Disease
Rabusin M, Andolina M, Maximova N, Lepore L, Parco S, Tuveri G, Jankovic G
Haematologica 2000 Nov;85(11 Suppl):81-5
Institute of Maternal and Child Health, Dept of Pediatrics, via dell'Istria 65/1, 34100, Trieste, Italy
PMID# 11268330; UI# 21166387
Background And Objectives
The aim of this study was to evaluate the tolerability and effectiveness of a Non-MyeloAblative conditioning regimen followed by autologous Hematopoietic Stem Cell infusion for the treatment of severe AutoImmune Diseases.
Design And Methods
From 1996 patients with severe AutoImmune Disease not responsive to conventional Immunosuppressive treatment were selected.
The patients' blood or marrow cells were harvested after incubation with Vincristine and Methylprednisolone. Two different ImmunoAblative conditioning regimens were employed.
The first used Cyclophosphamide (2500 mg/m2 in one day) and AntiLymphocyte Globulin (ALG) (15 vials/m2 in three days) and the second used Fludarabine (300 mg/m2 in two courses of 5 days) plus ALG (25 vials/m2 in 5 days).
Nineteen patients (14 female, 5 male) with severe AutoImmune Diseases were treated. Nine had a Rheumatologic Disorder (5 Juvenile Chronic Arthritis, 1 Rheumatoid Arthritis, 1 Systemic Vasculitis, 1 Sjogren's Syndrome, 1 Behct's Disease), 4 a Neurologic Disorder (3 Multiple Sclerosis, 1 Myasthenia), 3 a Haematologic Disease (2 Pure Red Cell Aplasia, 1 AutoImmune Thrombocytopenia), 2 had a Gastrointestinal Disease (1 Crohn's Disease, 1 AutoImmune Enteropathy) and 1 had a multiple AutoImmune Disorder.
There was no regimen-related toxicity and no opportunistic infections occurred. Ninety percent of the patients improved and/or had a complete remission after the procedure.
Fifty percent of the subjects went into complete or partial remission after a median follow-up of 15 months (range 3-25) while 50% relapsed after a median follow-up of 11 months, (range 6-16).
The incidence of relapse in the group treated with Fludarabine was lower (30%).
Interpretation And Conclusions
A Non-MyeloAblative conditioning regimen was able to induce persistent remission in some patients with severe AutoImmune diseases.
There was no mortality or morbidity related to the procedure. The extent of remission does, however, remain to be established.
Genetic Regulation Of Nerve Avulsion-Induced Spinal Cord Inflammation
Olsson T, Lundberg C, Lidman O, Piehl F
Ann N Y Acad Sci 2000;917:186-96
Karolinska Institute, CMM L08;04, Karolinska Hospital, NeuroImmunology Unit, Dept of Medicine, S-171 76 Stockholm, Sweden
PMID# 11268343; UI# 21166407
In the animal model for Multiple Sclerosis (MS), Experimental AutoImmune Encephalitis (EAE), Genetic loci correlating with incidence or severity of disease are located both within and outside of the Major Histocompatibility Complex (MHC).
Whereas polymorphisms within MHC Class I and II molecules are likely to be a major determinant of MHC Gene influence in rat EAE, it is still unclear how non-MHC Gene regions influence disease.
Genetic control of inflammation can hypothetically be either general or specific for a particular target tissue.
For the latter, Gene regulation of PathoMechanisms in the CNS could affect reactivity of Microglia or Astrocytes, local Cytokine/Chemokine production, or even Neuronal vulnerability.
We have obtained strong support for this notion by observations of rat strain-dependent variation in the inflammatory response after ventral root avulsion, a model in which mainly non-antigen-specific elements of the Immune System promote inflammation.
A comparison of strains with similar MHC haplotypes on different backgrounds and strains with different MHC haplotypes on the same background, respectively, demonstrates that the inflammatory phenotype is regulated mainly by non-MHC Genes.
Interestingly, different features of the inflammatory response, such as induction of MHC Class II expression, Glial activation, Cytokine expression, and Neuronal vulnerability, varied between rat strains and were largely independent of each other.
The Genetic control of several basic features of inflammation in the CNS is of great relevance not only for MS/EAE, but also for several other Neurological conditions with inflammatory components such as CerebroVascular and NeuroDegenerative Dieases and Trauma.
Susceptibility To AutoImmune Disease And Drug Addiction In Inbred Rats. Are There Mechanistic Factors In Common Related To Abnormalities In HypoThalamic-Pituitary-Adrenal Axis And Stress Response Function?
Wilder RL, Griffiths MM, Cannon GW, Caspi R, Remmers EF
Ann N Y Acad Sci 2000;917:784-96
National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, Bldg. 10, Room 9N240, Bethesda, Maryland 20892, USA
PMID# 11268408; UI# 21166468
DA and LEW inbred rats are extraordinarily susceptible to a wide range of experimental AutoImmune diseases.
These diseases include Rheumatoid Arthritis models such as Collagen-Induced Arthritis (CIA) and Adjuvant-Induced Arthritis (AIA), Multiple Sclerosis models such as Myelin-Basic-Protein (MBP)-induced Experimental AutoImmune EncephaloMyelitis (MBP-EAE).
And AutoImmune Uveitis models such as Retinal S antigen (SAG) and Interphotoreceptor-Retinoid-Binding-Protein (IRBP)-induced Experimental AutoImmune Uveitis (SAG-EAU and IRBP-EAU, respectively).
DA and LEW rats are also addiction-prone to various drugs of abuse, such as Cocaine. Moreover, they exhibit a variety of behavioral and biochemical characteristics that appear to be related to their susceptibility to addiction.
By contrast, F344 and BN rats show quite different phenotypes. They are relatively resistant to CIA, AIA, MBP-EAE, SAG-EAU, and IRBP-EAU, and they are relatively resistant to addiction.
Interestingly, both DA and LEW rats, in contrast to F344 and BN rats, have abnormalities in HypoThalamic-Pituitary-Adrenal (HPA) Axis function.
For example, circadian production of CorticoSteroids is very abnormal in DA and LEW rats; that is, they exhibit minimal circadian variation in CorticoSterone levels.
Since CorticoSteroids potentially have significant influences on Immune function and AutoImmune Disease susceptibility and may also influence sensitivity to drugs of abuse, we have begun to dissect Genetic control of these various phenotypic differences, focusing initially on the regulation of AutoImmune Disease expression.
Using genomewide scanning techniques involving F2 crosses of DA x F344 (CIA and AIA), DA x BN (CIA), and LEW x F344 [IRBP-EAU and Streptococcal-Cell-Wall Arthritis (SCWA)], we have identified, to date, 14 genomic regions [Quantitative Trait Loci (QTL)] that regulate disease expression in these crosses.
Development and analysis of QTL-congenic rats involving these loci are in progress and should permit us to address the relationships among AutoImmune disease susceptibility, drug addiction, and HPA axis and stress response function.
These initial data, however, indicate that the Genetic control of the AutoImmune disease traits is highly complex.
Control Of The Cell Survival/Death Decision By Cannabinoids
Guzman M, Sanchez C, Galve-Roperh I
J Mol Med 2001;78(11):613-25
Complutense University, School of Biology, Dept of BioChemistry and Molecular Biology I, Madrid, Spain
PMID# 11269508; UI# 21166016
Cannabinoids, the active components of Cannabis sativa (Marijuana), and their derivatives produce a wide spectrum of Central and Peripheral effects, some of which may have clinical application.
The discovery of specific Cannabinoid receptors and a family of endogenous Ligands of those receptors has attracted much attention to Cannabinoids in recent years. One of the most exciting and promising areas of current Cannabinoid research is the ability of these compounds to control the cell survival/death decision.
Thus Cannabinoids may induce proliferation, growth arrest, or Apoptosis in a number of cells, including Neurons, Lymphocytes, and various transformed Neural and NonNeural Cells.
The variation in drug effects may depend on experimental factors such as drug concentration, timing of drug delivery, and type of cell examined.
Regarding the Central Nervous System, most of the experimental evidence indicates that Cannabinoids may protect Neurons from toxic insults such as Glutamaergic overstimulation, Ischemia and Oxidative damage.
In contrast, Cannabinoids induce apoptosis of Glioma Cells in culture and regression of malignant Gliomas in vivo. Breast and Prostate Cancer Cells are also sensitive to Cannabinoid-induced antiproliferation.
Regarding the Immune System, low doses of Cannabinoids may enhance cell proliferation, whereas high doses of Cannabinoids usually induce growth arrest or Apoptosis.
The NeuroProtective effect of Cannabinoids may have potential clinical relevance for the treatment of NeuroDegenerative Disorders such as Multiple Sclerosis, Parkinson's Disease, and Ischemia/Stroke.
Whereas their growth-inhibiting action on transformed cells might be useful for the management of malignant Brain Tumors.
Ongoing investigation is in search for Cannabinoid based therapeutic strategies devoid of nondesired Psychotropic effects.