Use of stem cells for the treatment of multiple sclerosis

The reported evidence of neurodegeneration in multiple sclerosis (MS) may explain the lack of efficacy of the currently used immunomodulating modalities and the irreversible axonal damage, which results in accumulating disability. To date, efforts for neuroprotective treatments have not been successful in clinical studies in other CNS diseases. Therefore, for MS, the use of stem cells may provide a logical solution, since these cells can migrate locally into the areas of white-matter lesions (plaques) and have the potential to support local neurogenesis and rebuilding of the affected myelin. This is achieved both by support of the resident CNS stem cell repertoire and by differentiation of the transplanted cells into neurons and myelin-producing cells (oligodendrocytes). Stem cells were also shown to possess immunomodulating properties, inducing systemic and local suppression of the myelin-targeting autoimmune lymphocytes. Several types of stem cells (embryonic and adult) have been described and extensively studied in animal models of CNS diseases and the various models of MS (experimental autoimmune encephalomyelitis [EAE]). In this review, we summarize the experience with the use of different types of stem cells in CNS disease models, focusing on the models of EAE and describe the advantages and disadvantages of each stem cell type for future clinical applications in MS.     

Increased X-linked inhibitor of apoptosis protein (XIAP) expression exacerbates experimental autoimmune encephalomyelitis (EAE)

Dysregulated apoptotic signaling has been implicated in most forms of cancer and many autoimmune diseases, such as multiple sclerosis (MS). We have previously shown that the anti-apoptotic protein X-linked inhibitor of apoptosis (XIAP) is elevated in T cells from mice with experimental autoimmune encephalomyelitis (EAE). In MS and EAE, the failure of autoimmune cells to undergo apoptosis is thought to exacerbate clinical symptoms and contribute to disease progression and CNS tissue damage. Antisense-mediated knockdown of XIAP, in vivo, increases the susceptibility of effector T cells to apoptosis, thus attenuating CNS inflammation and thereby alleviating the clinical signs of EAE. We report for the first time, generation of transgenic mice whereby the ubiquitin promoter drives expression of XIAP (ubXIAP), resulting in increased XIAP expression in a variety of tissues, including cells comprising the immune system. Transgenic ubXIAP mice and wild-type (WT) littermates were immunized with myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freund's adjuvant and monitored daily for clinical symptoms of EAE over a 21-day period. The severity of EAE was increased in ubXIAP mice relative to WT-littermates, suggesting that XIAP overexpression enhanced the resistance of T cells to apoptosis. Consistent with this finding, T cells derived from MOG35-55-immunized ubXIAP mice and cultured in the presence of antigen were more resistant to etoposide-mediated apoptosis compared to WT-littermates. This work identifies XIAP is an important apoptotic regulator in EAE and a potential pharmacological target for treating autoimmune diseases such as MS.     

Estrogen treatment induces a novel population of regulatory cells, which suppresses experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a debilitating neurological disease characterized by a progressive loss of motor and sensory function, eventually leading to paralysis and death. The primary cause of neurological impairment is demyelination of the central nervous system (CNS) caused by an inflammatory autoimmune response. Previous studies have shown that the severity of MS is reduced during pregnancy, suggesting that the increased level of sex hormones may reduce the autoimmune response. Recently, we have shown that estrogen treatment confers protection from experimental autoimmune encephalomyelitis (EAE), which is an animal model for MS. However, the cellular basis of estrogen's action remains unknown. In the current study, we demonstrate that estrogen treatment led to the induction of a novel subpopulation of regulatory cells in spleen and CNS, which also occurs naturally in pregnant mice. These previously uncharacterized cells display a low level expression of CD45 (CD45(dim)) and no detectable expression of many cell surface markers related to TCR signaling, including CD3 and TCR. However, these cells retained expression of VLA-4, an extracellular protein involved in cellular migration. Several lines of evidence suggest that these novel cells, defined as CD45(dim)VLA-4(+) cells, may play a role in the protective effects of estrogen in EAE. Injection of purified CD45(dim)VLA-4(+) cells conferred protection from spontaneous EAE (Sp-EAE). In contrast, injection of CD45(high)VLA-4(+) cells exacerbated the disease course. CD45(dim)VLA-4(+) cells also suppressed antigen-specific proliferation of primed lymphocytes in coculture. A better understanding of how CD45(dim)VLA-4(+) cells suppress the harmful immune response of EAE may help in explaining the induction of immune tolerance during pregnancy and lead to novel therapeutic approaches to combat MS and other autoimmune diseases.     

MiR-30a Positively Regulates the Inflammatory Response of Microglia in Experimental Autoimmune Encephalomyelitis

Multiple sclerosis(MS) is a classical inflammatory demyelinating disease of the central nervous system(CNS). Microglia are the main resident immune cells in the CNS and are closely associated with the pathogenesis of MS.In the present study, we found that mi R-30 a was highly expressed in jellyfish-like microglia in chronic active lesions of MS patients, as well as in the microglia of mice with experimental autoimmune encephalomyelitis(EAE) at the chronic phase. In vitro, the conditioned supernatant of mouse microglia overexpressing miR-30 a promoted the apoptosis of oligodendrocyte precursor cells(OPCs), and inhibited OPC differentiation. In vivo, overexpressing miR-30 a in transplanted microglia exacerbated the progression of EAE.Overexpression and knock-down experiments in primary cultured mouse microglia showed that mi R-30 a increased the expression of IL-1 b and i NOS, which are pro-inflammatory, while inhibiting the expression of Ym-1 and CD206.Mechanistically, mi R-30 a inhibited the expression of Ppargc1 b, which is the co-activator of peroxisome proliferator-activated receptor gamma, resulting in pro-inflammatory effects. Our work shows that mi R-30 a is an important regulator of the inflammatory response in microglia, and may be a promising therapeutic target for inflammatory diseases like MS in the CNS.     

β-Lapachone ameliorization of experimental autoimmune encephalomyelitis

β-Lapachone is a naturally occurring quinine, originally isolated from the bark of the lapacho tree (Tabebuia avellanedae) which is currently being evaluated in clinical trials for the treatment of cancer. In addition, recent investigations suggest its potential application for treatment of inflammatory diseases. Multiple sclerosis (MS) is an autoimmune disorder characterized by CNS inflammation and demyelination. Reactive T cells including IL-17 and IFN-γ-secreting T cells are believed to initiate MS and the associated animal model system experimental autoimmune encephalomyelitis (EAE). IL-12 family cytokines secreted by peripheral dendritic cells (DCs) and CNS microglia are capable of modulating T-cell phenotypes. The present studies demonstrated that β-lapachone selectively inhibited the expression of IL-12 family cytokines including IL-12 and IL-23 by DCs and microglia, and reduced IL-17 production by CD4⁺ T-cells indirectly through suppressing IL-23 expression by microglia. Importantly, our studies also demonstrated that β-lapachone ameliorated the development on EAE. β-Lapachone suppression of EAE was associated with decreased expression of mRNAs encoding IL-12 family cytokines, IL-23R and IL-17RA, and molecules important in Toll-like receptor signaling. Collectively, these studies suggest mechanisms by which β-lapachone suppresses EAE and suggest that β-lapachone may be effective in the treatment of inflammatory diseases such as MS.     

The potential use of stem cells in multiple sclerosis: an overview of the preclinical experience

The reported neurodegeneration process in multiple sclerosis may explain the lack of efficacy of the currently used immunomodulating modalities and the irreversible axonal damage, which results in accumulating disability. Efforts for neuroprotective treatments have not been, so far, successful in clinical studies in other CNS diseases. Therefore, for MS, the use of stem cells may provide a logical solution, since these cells can migrate locally into the areas of white matter lesions (plaques) and have the potential to support local neurogenesis and rebuilding of the affected myelin. This may be achieved both by support of the resident CNS stem cells repertoire and by differentiation of the transplanted cells into neurons and myelin-producing cells (oligodendrocytes). Stem cells were also shown to possess immunomodulating properties, inducing systemic and local suppression of the myelin-targeting autoimmune lymphocytes. Several types of stem cells (embryonic and adult) have been described and extensively studied in animal models of CNS diseases. In this review, we summarize the experience with the use of different types of stem cells in the animal models of MS (EAE) and we describe the advantages and disadvantages of each stem cell type for future clinical applications in MS.     

K+ channel alterations in the progression of experimental autoimmune encephalomyelitis

Voltage-gated K(+) (Kv) channels play critical roles not only in regulating synaptic transmission and intrinsic excitability of neurons, but also in controlling the function and proliferation of other cells in the central nervous system (CNS). The non-specific Kv channel blocker, 4-AminoPyridine (4-AP) (Dalfampridine, Ampyra?), is currently used to treat multiple sclerosis (MS), an inflammatory demyelinating disease. However, little is known how various types of Kv channels are altered in any inflammatory demyelinating diseases. By using established animal models for MS, experimental autoimmune encephalomyelitis (EAE), we report that expression and distribution patterns of Kv channels are altered in the CNS correlating with EAE severity. The juxtaparanodal (JXP) targeting of Kv1.2/Kvβ2 along myelinated axons is disrupted within demyelinated lesions in the white matter of spinal cord in EAE. Moreover, somatodendritic Kv2.1 channels in the motor neurons of lower spinal cord significantly decrease correlating with EAE severity. Interestingly, Kv1.4 expression surrounding lesions is markedly up-regulated in the initial acute phase of both EAE models. Its expression in glial fibrillary acidic protein (GFAP)-positive astrocytes further increases in the remitting phase of remitting-relapsing EAE (rrEAE), but decreases in late chronic EAE (chEAE) and the relapse of rrEAE, suggesting that Kv1.4-positive astrocytes may be neuroprotective. Taken together, our studies reveal myelin-dependent and -independent alterations of Kv channels in the progression of EAE and lay a solid foundation for future study in search of a better treatment for MS.     

Recent advances in the immunopathology of experimental autoimmune encephalomyelitis: With special reference to cytokine production in the central nervous system

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease that can be induced by immunization with encephalitogenic antigens such as myelin basic protein. Recent in vitro studies have demonstrated that cytokines play an important role in immune reactions in the central nervous system (CNS), suggesting that cytokines released by infiltrating cells and glial cells may contribute to the pathogenesis of EAE. In this review, we focus on the interactions between infiltrating cells and brain cells during the inflammatory process in EAE and discuss the roles of cytokines in the CNS. After immunization with proper myelin antigens, encephalitogenic T cells increase in number and infiltrate the CNS parenchyma via the subarachnoid space or the blood vessels. Once inflammatory cells infiltrate the CNS, microglia and astrocytes are activated, and some of these cells proliferate in response to cytokines released by infiltrating cells. Following this, activated microglia present antigens to induce T cell proliferation and cytokine production. In contrast, astrocytes induce T cell unresponsiveness, probably due to a lack of costimulatory signals. Furthermore, infiltrating T cells are the main producers of Th1 cytokines and are involved in T cell-brain cell interactions. This cascade of events indicates that immune reactions take place in the CNS, although the CNS has previously been considered to be an immunologically privileged site. Based on these findings, we also discuss the feasibility of using various cytokines to stimulate the immunomodulation of brain inflammation as a treatment for autoimmune demyelinating diseases.     

Protective effects of microglia in multiple sclerosis

The role of microglia in demyelinating neurodegenerative diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) is still controversial. Although microglial cells are known as the professional phagocytes and executer of innate immunity in the central nervous system (CNS), it is believed that microglia are rather neurotoxic in these diseases. However, there is recent evidence indicating that microglia could also exert a neuroprotective function in MS and EAE. First evidence for the protective effect of immune cells in CNS diseases emerged from studies in invertebrates. In the medicinal leech, the process of regeneration begins with rapid activation and accumulation of phagocytic glial cells at the lesion site followed by phagocytosis of damaged tissue by these cells which promoted robust neural regeneration. In vertebrates, several lines of evidence demonstrate that microglia are also involved in neuroprotection by the secretion of soluble mediators that trigger neural repair and usually contribute to the creation of an environment conductive for regeneration. The efficient removal of apoptotic cells and clearance of debris at the lesion site and the recruitment of stem cell populations as well as the induction of neurogenesis are directly correlated. These findings suggest that microglia play a major role in creating a microenvironment for repair and regenerative processes in demyelinating neuroinflammatory diseases.     

Apoptosis of inflammatory cells in immune control of the nervous system: role of glia

The elimination of inflammatory cells within the central nervous system (CNS) by apoptosis plays an important role in protecting the CNS from immune-mediated damage. T cells, B cells, macrophages, and microglia all undergo apoptosis in the CNS. The apoptotic elimination of CNS-reactive T cells is particularly important, as these cells can recruit and activate other inflammatory cells. T-cell apoptosis contributes to the resolution of CNS inflammation and clinical recovery from attacks of experimental autoimmune encephalomyelitis (EAE), an animal model of the demyelinating disease multiple sclerosis (MS). T-cell apoptosis in the CNS in EAE occurs in both an antigen-specific and an antigen-nonspecific manner. In antigen-specific T-cell apoptosis, it is proposed that T cells that recognize their antigen in the CNS, such as CNS-reactive T cells, are deleted by the process of activation-induced apoptosis after activation of the T-cell receptor. This may result from the ligation of T-cell death receptors (such as CD95 (Fas) or tumor necrosis factor (TNF) receptor 1) by CD95 ligand (CD95L) or TNF expressed by the same T cell or possibly by microglia, astrocytes or neurons. Inadequate costimulation of the T cell by antigen-presenting glial cells may render T cells susceptible to activation-induced apoptosis. T cells expressing CD95 may also die in an antigen-nonspecific manner after interacting with glial cells expressing CD95L. Other mechanisms for antigen-nonspecific T-cell apoptosis include the endogenous release of glucocorticosteroids, deprivation of interleukin-2, and the release of nitric oxide by macrophages or glia. Apoptosis of autoreactive T cells in the CNS is likely to be important in preventing the development of autoimmune CNS diseases such as MS.     

Inflammation induced neurological handicap processes in multiple sclerosis: new insights from preclinical studies

Multiple sclerosis (MS) is described as originating from incompletely explained neuroinflammatory processes, dysfunction of neuronal repair mechanisms and chronicity of inflammation events. Blood-borne immune cell infiltration and microglia activation are causing both neuronal destruction and myelin loss, which are responsible for progressive motor deficiencies, organic and cognitive dysfunctions. MRI as a non-invasive imaging method offers various ways to visualise de- and remyelination, neuronal loss, leukocyte infiltration, blood–brain barrier modification and new sensors are emerging to detect inflammatory lesions at an early stage. We describe studies performed on experimental autoimmune encephalomyelitis (EAE) animal models of MS that shed new light on mechanisms of functional impairments to understand the neurological handicap in MS. We focus on examples of neuroinflammation-mediated inhibition of CNS repair involving adult neurogenesis in the sub-ventricular zone and hippocampus and such experimentally observed inhibitions could reflect deficient plasticity and activation of compensatory mechanisms in MS. In parallel with cognitive decline, organic deficits such as bladder dysfunction are described in most of MS patients. Neuropharmacological interventions, electrical stimulation of nerves, MRI and histopathology follow-up studies helped in understanding the operating events to remodel the neurological networks and to compensate the inflammatory lesions both in spinal cord and in cortical regions. At the molecular level, the local production of reactive products is a well-described phenomenon: oxidative species disturb cellular physiology and generate new molecular epitopes that could further promote immune reactions. The translational research from EAE animal models to MS patient cohorts helps in understanding the mechanisms of the neurological handicap and in development of new therapeutic concepts in MS.     

Activation of calpain and caspase pathways in demyelination and neurodegeneration in animal model of multiple sclerosis

Experimental autoimmune encephalomyelitis (EAE), a widely recognized animal model of multiple sclerosis (MS), is highly useful for studying inflammation, demyelination, and neurodegeneration in the central nervous system (CNS). EAE exhibits many similarities with MS, which is a chronic inflammatory disease affecting CNS white matter in humans. Various studies have indicated that EAE is a particularly useful animal model for understanding both the mechanisms of immune-mediated CNS pathology and also the progressive clinical course of MS. Demyelination and axonal dysfunction have previously been shown in MS and EAE but current evidences indicate that axonal damage and neuron death also occur, demonstrating that these diseases harbor a neurodegenerative component. Recent studies also have shown that the activation of calpain and caspase pathways contribute to the apoptotic death of oligodendrocytes and neurons, promoting the pathological events leading to neurological deficits. Apoptosis is involved in the disease-regulating as well as in the disease-promoting processes in EAE. This review discusses the major involvement of calpain and caspase pathways in causing demyelination and neurodegeneration in EAE animals.     

Neurogenesis,inflammation and behavior

Before the 1990s it was widely believed that the adult brain was incapable of regenerating neurons. However, it is now established that new neurons are continuously produced in the dentate gyrus of the hippocampus and olfactory bulb throughout life. The functional significance of adult neurogenesis is still unclear, but it is widely believed that the new neurons contribute to learning and memory and/or maintenance of brain regions by replacing dead or dying cells. Many different factors are known to regulate adult neurogenesis including immune responses and signaling molecules released by immune cells in the brain. While immune activation (i.e., enlargement of microglia, release of cytokines) within the brain is commonly viewed as a harmful event, the impact of immune activation on neural function is highly dependent on the form of the immune response as microglia and other immune-reactive cells in the brain can support or disrupt neural processes depending on the phenotype and behavior of the cells. For instance, microglia that express an inflammatory phenotype generally reduce cell proliferation, survival and function of new neurons whereas microglia displaying an alternative protective phenotype support adult neurogenesis. The present review summarizes current understanding of the role of new neurons in cognition and behavior, with an emphasis on the immune system’s ability to influence adult hippocampal neurogenesis during both an inflammatory episode and in the healthy uninjured brain. It has been proposed that some of the cognitive deficits associated with inflammation may in part be related to inflammation-induced reductions in adult hippocampal neurogenesis. Elucidating how the immune system contributes to the regulation of adult neurogenesis will help in predicting the impact of immune activation on neural plasticity and potentially facilitate the discovery of treatments to preserve neurogenesis in conditions characterized by chronic inflammation.     

Multiple sclerosis -- a coordinated immune attack across the blood brain barrier

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS). The acquired immune system plays a central role in the pathogenesis of MS although target antigens and effector mechanisms are still poorly defined. Studies in animal models of infectious or autoimmune encephalomyelitis suggest that the acquired immune response targeting the CNS in MS originates from the periphery. Both T and B cells undergo activation and maturation in the lymphoid system allowing them to cross the blood brain barrier and infiltrate CNS tissue. Within the CNS, they require a local proinflammatory milieu contributed by macrophages and microglia to mediate their effector function which ultimately leads to damage of myelin sheath, oligodendrocytes, and neurons. In the current review, we elucidate the role of the immune system in MS with particular emphasis on activation and migration of immune cells to the CNS, the role of CNS cells in the inflammatory process and the contribution of the immune system to damage and repair. Based on these considerations we discuss new strategies to investigate pathogenetic pathways in multiple sclerosis.     

Vascular endothelial growth factor is expressed in multiple sclerosis plaques and can induce inflammatory lesions in experimental allergic encephalomyelitis rats

The active lesions in multiple sclerosis (MS) are characterized by blood-brain-barrier (BBB) breakdown, upregulation of adhesion molecules on capillary endothelial cells, and perivascular inflammation, suggesting that altered vessel permeability and activated endothelial cells are involved in the pathogenesis of the disease. Vascular endothelial growth factor (VEGF) mediates multiple aspects of blood vessel physiology, including regulation of growth, permeability, and inflammation. To investigate a possible relationship between VEGF expression and CNS autoimmune disease, we examined VEGF expression in MS plaques compared to normal white matter by immunohistochemistry and in situ hybridization. VEGF expression was consistently upregulated in both acute and chronic MS plaques. We also examined VEGF expression during the course of experimental allergic encephalomyelitis (EAE) in rats. VEGF-positive cells with astrocytic morphology increased in the spinal cord during the development of EAE and were found in association with inflammatory cells. Furthermore, intracerebral infusion of VEGF in animals previously immunized with myelin basic protein induced an inflammatory response in the brain, whereas infusion of vehicle, or infusion of VEGF in naive animals, did not. These results suggest that overexpression of VEGF may exacerbate the inflammatory response in autoimmune diseases of the CNS by inducing focal BBB breakdown and migration of inflammatory cells into the lesions.     

Activating transcription factor 6α deficiency exacerbates oligodendrocyte death and myelin damage in immune‐mediated demyelinating diseases

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) play a critical role in immune‐mediated demyelinating diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), by regulating the viability of oligodendrocytes. Our previous studies show that activation of the PERK branch of the UPR protects myelinating oligodendrocytes against ER stress in young, developing mice that express IFN‐γ, a key pro‐inflammatory cytokine in MS and EAE, in the CNS. Several studies also demonstrate that PERK activation preserves oligodendrocyte viability and function, protecting mice against EAE. While evidence suggests activation of the ATF6α branch of the UPR in oligodendrocytes under normal and disease conditions, the effects of ATF6α activation on oligodendrocytes in immune‐mediated demyelinating diseases remain unknown. Herein, we showed that ATF6α deficiency had no effect on oligodendrocytes under normal conditions. Interestingly, we showed that ATF6α deficiency exacerbated ER stressed‐induced myelinating oligodendrocyte death and subsequent myelin loss in the developing CNS of IFN‐γ‐expressing mice. Moreover, we found that ATF6α deficiency increased EAE severity and aggravated EAE‐induced oligodendrocyte loss and demyelination, without affecting inflammation. Thus, these data suggest the protective effects of ATF6α activation on oligodendrocytes in immune‐mediated demyelinating diseases.     

Immunopathogenesis of multiple sclerosis: concepts and controversies

Hundred and fifty years after the discovery of multiple sclerosis (MS), neither the etiology nor the mechanism of disease is fully charted, and current treatment has only modest effect. The conceptual understanding of MS rests on the animal model experimental autoimmune encephalomyelitis (EAE). Based on 70 years experience with EAE, it is widely believed that MS is an inflammatory attack on myelin and neurons orchestrated by myelin specific T cells. However, evidence supporting a key role for myelin specific T cells in MS is weak, the model fails to explain how immune self-tolerance is broken, and the peculiar B cell response of MS is poorly reflected in EAE. The pathogenesis of MS should therefore be studied in tissue samples and cells from MS patients, as close to the diseased organ as possible. Studies on lymphocytes from CSF of MS patients suggest that viral infections may be involved in T cell activation, and that intrinsic collaboration between T and B cells could sustain the immune response. These observations could explain the perpetuating immune response in MS in the absence of an overt antigen.     

Tuftsin‐driven experimental autoimmune encephalomyelitis recovery requires neuropilin‐1

Experimental autoimmune encephalomyelitis (EAE) is an animal model of demyelinating autoimmune disease, such as multiple sclerosis (MS), which is characterized by central nervous system white matter lesions, microglial activation, and peripheral T‐cell infiltration secondary to blood–brain barrier disruption. We have previously shown that treatment with tuftsin, a tetrapeptide generated from IgG proteolysis, dramatically improves disease symptoms in EAE. Here, we report that microglial expression of Neuropilin‐1 (Nrp1) is required for tuftsin‐driven amelioration of EAE symptoms. Nrp1 ablation in microglia blocks microglial signaling and polarization to the anti‐inflammatory M2 phenotype, and ablation in either the microglia or immunosuppressive regulatory T cells (Tregs) reduces extended functional contacts between them and Treg activation, implicating a role for microglia in the activation process, and more generally, how immune surveillance is conducted in the CNS. Taken together, our findings delineate the mechanistic action of tuftsin as a candidate therapeutic against immune‐mediated demyelinating lesions. GLIA 2016;64:923–936     

Inhibitor of apoptosis protein (IAP) profiling in experimental autoimmune encephalomyelitis (EAE) implicates increased XIAP in T lymphocytes

In multiple sclerosis (MS) and its widely accepted animal model, experimental autoimmune encephalomyelitis (EAE), the failure of autoreactive immune cells to undergo apoptosis is thought to contribute to CNS tissue damage and disease progression. Promoting apoptosis of myelin-reactive immune cells in diseases such as MS, may delay disease progression and decrease the frequency and severity of relapses. X-linked inhibitor of apoptosis (XIAP) is a potent anti-apoptotic protein that inhibits intrinsic, extrinsic, and c-Jun amino-terminal kinase mediated apoptosis and was the only member of the inhibitor of apoptosis (IAP) family upregulated in whole blood from EAE mice. Similar increases in XIAP were also observed in both peripheral and encephalitogenic T lymphocytes. Increased XIAP expression in T cells within areas of demyelination in the CNS suggests that XIAP may be enhancing cell survival and thereby contributing to disease pathology.