While the AIRE expression in β cells did induce TRA expression, when compared with thymic medullary epithelial cells, the authors found minor overlap in the

gene expression patterns. This suggests a cell specific aspect to the expressed AIRE and that AIRE has the general ability to promote the TRA expression regardless of where it may be expressed 34. Prompted by our in vitro observations, Selleckchem Ibrutinib we generated a panel of chimeric mice to test whether the ectopic expression of AIRE through transfer of transduced BM can influence the development of EAE. As previously published, we confirmed that the ectopic expression of MOG following transplantation of BM transduced by retrovirus encoding Mog prevented EAE development 29. While transplantation of Aire-transduced BM did not completely protect mice from EAE development, there was significant retardation in the induction of EAE compared with control groups. In our earlier studies with ectopic expression of MOG, we observed evidence of thymic deletion of MOG35–55-specific T cells 29. We predict that a similar mechanism may also be active here but this needs to be confirmed. While the ectopic gene expression in our system

is not restricted to any particular cell lineage due to the ubiquitous nature of the retroviral promoter, dendritic cells would be considered the main BM-derived instigator this website of tolerance 41, 42 through uptake and presentation of antigen 43, 44. However, it has been shown that if dendritic cells can directly express antigen, then tolerance to that antigen can also ensue 45. Given

this, we suggest that MOG expressed within dendritic cells derived from transduced BM could drive tolerance within the thymus through deletion and/or BCKDHB possibility through the generation of T regulatory cells 46. Our model will also promote the ectopic AIRE expression in the range of peripherally destined cells such as dendritic cells, macrophages and B cells, and thus cannot be overlooked at this stage as another potential avenue for mechanisms capable of promoting tolerance. Finally, we cannot rule out the possibility that the ectopic expression of Aire may be exerting its effect on EAE independently of TRA expression. AIRE is also known to transcriptionally activate or repress non-TRA, such as cytokine and cytokine receptors 47 and thus could influence immune responses. Whether a similar effect is occurring in our model of ectopically expressed Aire is not known at this point. Autoimmune diseases remain a major clinical challenge and current treatments are non-curative and often involve non-specific immunosuppressive regimes. The prospect of developing strategies aimed at delivering antigen-specific tolerance would be a major advance in this field.

Denervated muscle fibres of sALS and NMA cases and SOD1 mice showed diffusely increased STIM1 immunoreactivity along with ubiquitinated material. In addition,

distinct focal accumulations of STIM1 were observed in target structures within denervated fibres of Talazoparib sALS and other NMA as well as SOD1 mouse muscles. Large STIM1-immunoreactive structures were found in ALS-8 patient muscle harbouring the P56S mutation in the ER protein VAPB. These findings suggest that STIM1 is involved in several ways in the reaction of muscle fibres to denervation, probably reflecting alterations in calcium homeostasis in denervated muscle fibres. “
“In this case report, for the first time, we provide descriptive cliniconeuropathological features of a case of familial amyotrophic lateral sclerosis (familial ALS, FALS) with p.N352S mutation in TARDBP. The present Japanese patient (Figure 1, II-4, the proband) was born in Wakayama Prefecture. At 74 years, he experienced weakness in the muscles of both hand. He visited our neurology department RGFP966 solubility dmso with complaints of impaired fine motor skills of both hands at 76 years, and his neurological examination showed muscle weakness and muscular atrophy of both hands. At 77 years, his muscle weakness descended to both thighs, leading to difficulty

in walking by himself. While his tongue revealed slight atrophy and fasciculation, there were no

detectable upper Thymidylate synthase motor neurone (UMN) signs, cognitive impairment, dysphagia, dysarthria, sensory disturbances, or gait disturbances. Electromyography disclosed active denervation of muscle potentials in both the upper and lower extremities, and he was diagnosed with ALS. His respiratory function gradually worsened, and he died of respiratory failure at 78 years, 4 years after onset. In the patient’s pedigree, his niece (III-2), who is now 60 years old, was also affected by ALS. She had complaints of muscle weakness of the lower extremities at 45 years and is currently on ventilatory support. She can still communicate using lip movements. Informed consent for the gene study was obtained from the patient and his family. Genomic DNA was extracted from peripheral blood leucocytes using standard methods. All exons and exon–intron boundaries of copper/zinc superoxide dismutase (SOD1) and TARDBP were analysed by polymerase chain reaction and direct sequencing, as previously reported [1,2]. TARDBP analysis identified a c.1055A>G heterozygous missense mutation at codon 352 (p.N352S) and no mutation of SOD1. The present study was approved by the ethics committees of all participating institutions. Neuropathologically, brain weight after fixation was 1295 g. Macroscopically, both the cerebrum and cerebellum were preserved. In the brainstem, medullary pyramid volumes were slightly decreased.

High expression levels of BTN3 transcripts could be found in human lymphoid tissues, mainly spleen, LNs and peripheral blood lymphocytes (PBLs) 1. Using an anti-CD277 monoclonal antibody, it was also demonstrated that BTN3A was expressed on most immune cells, including not only T and B lymphocytes, but also NK cells, monocytes,

DCs, as well as hematopoietic precursors and some tumor www.selleckchem.com/products/epacadostat-incb024360.html cell lines 1. Research on the counter-receptor of BTN3A showed that neither CD28, CTLA-4, ICOS, PD-1 nor BTLA were involved, and, except from some (but not all) acute T leukemia cell lines, was absent from both resting and activated T cells. Similar experiments were performed with BTN2A and showed that BTN2A mRNA was expressed in most human tissues, but protein expression was significantly lower in leukocytes. These experiments also revealed that a particular glycosylated form of BTN2A1 binds a lectin molecule, DC-SIGN, found on DCs, confirming the involvement of the BTN family as co-regulators of the immune system 10. Furthermore, the binding of human BTN2A1 to DC-SIGN was also dependent on heavy glycosylation of the receptor when expressed by tumor cells. In two recent studies, the recombinant murine BTNL2 protein bound an unidentified receptor on B cells and T cells 11, distinct from the known receptors of the B7 molecules Z-VAD-FMK nmr 12. Both groups demonstrated that the activation of mouse T cells,

through TCR engagement, was inhibited by the ligation of BTNL2 with its putative receptor on T cells. Recently, a report proposed that BTN3A1 is an additional co-inhibitor receptor of T-cell activation 13. However, the expression of BTN3A1 on lymphocytes as well

as on NK cells prompted us to investigate Thiamine-diphosphate kinase whether BTN3A1 was involved in the regulation of innate effectors (NK cells) as well as T lymphocytes ant to explore the potential role of BTN3 (CD277) on the regulation of T lymphocyte and NK cell activation. Our results show that CD277-triggering in CD4+ T cells considerably enhances TCR-induced signaling, cytokine production and CD4+ T-cell proliferation. In contrast, CD277 triggering is not involved in CD16- or NKp46-induced NK-cell activation. The differential behaviour of CD277 in these two immune cell types prompted us to investigate the relative expression of the different BTN3 isoforms in both T cells and NK cells. To identify possible differences at the protein level, detection of CD277 surface expression was performed on several T and NK differentiation subsets from healthy donors (n=4). Using multi-parametric flow cytometry, CD3+CD4+, CD3+CD8+ and NK cell populations were analyzed (see Supporting Information, Figs. 1 and 2). Staining with the CD277 mAb reveals a strong expression of CD277 in all cell types CD4+ helper T cells, cytolytic CD8+ T cells and NK cells (Figs. 1B and 2B).

Subsequently, cells were allowed to adhere to poly-L-lysine-coated glass slides, mounted with anti-bleach reagent and analyzed by confocal microscopy (Leica AOBS SP2 confocal laser scanning microscope system containing a DM-IRE2 microscope with glycerol objective lens (PL APO 63×/NA1.30) was used; images were acquired using Leica confocal software (version 2.61)). We thank the staff of our animal facility for the care of the animals used in this study. We also thank Dr. B. J. Appelmelk

for kindly providing us the PAA-biotinylated glycans and Dr. S. van Vliet for critically reading the manuscript. S. K. S. was supported by NWO Mozaïek grant 017.001.136 from the Dutch Scientific Research program, E. S. by grant of the AICR 07-0163 and W. W. U. by grant SII071030 of SenterNovem. Conflict of interest: The authors declare no financial or commercial conflict of interest. Detailed facts of importance to specialist readers are published as ”Supporting Sirolimus Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made

available as submitted by the authors. “
“Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immunodeficiencies in adults. They comprise a heterogeneous group of pathologies, with frequent non-infectious complications in addition to the bacterial infections MK-8669 clinical trial that usually characterize their presentation. Complications include a high risk of malignancy, especially lymphoma and gastric cancer. Helicobacter pylori infection and pernicious anaemia are risk predictors for gastric cancer in the general population and probably in patients with CVIDs. Screening for gastric cancer in a high-risk

population appears to improve survival. Given the increased risk of gastric cancer in patients with CVIDs and prompted by a case of advanced gastric malignancy in a patient with a CVID and concomitant pernicious anaemia, we performed a review of the literature for gastric cancer and conducted a cohort study of gastric pathology in 116 patients with CVIDs under long-term follow-up in Oxford. Regardless of the presence of pernicious anaemia or H. pylori infection, patients with CVIDs have a 10-fold increased risk of gastric cancer Montelukast Sodium and are therefore a high-risk population. Although endoscopic screening of all patients with CVIDs could be considered, a more selective approach is appropriate and we propose a surveillance protocol that should reduce modifiable risk factors such as H. pylori, in order to improve the management of patients with CVIDs at risk of gastric malignancy. The common variable immunodeficiency disorders (CVIDs) are a heterogeneous group of diseases characterized by primary antibody failure, although many patients with CVIDs also exhibit defects in cell-mediated immunity suggesting immune dysregulation [1]. Such a diagnosis requires the exclusion of other known causes of hypogammaglobulinaemia [2].

We found that the surface protein A (SasA) of S. aureus could protect mice from lethal challenge of the bacteria. Staphylococcus aureus, a conditional pathogenic Gram-positive bacterium, is the leading cause of bloodstream, lower respiratory tract and skin/soft-tissue infections, accounting for 20–25% of all nosocomial infections (1,2,3). Bacteremia is the most prevalent type of S. aureus infections in hospitalized patients, followed by lower respiratory tract infections and skin/soft tissue infections (4,5). S. aureus is able

to adapt to new antibiotics and acquire antibiotic resistance (6). The extensive use of antibiotics has resulted in increased resistance among S. aureus clinical isolates. In patients with large area burn, it was found that more than 90% of S. aureus isolates were resistant to 11 types of antibiotics, including ampicillin, cefazolin, ciprofloxacin, gentamicin, levofloxacin, clidamycin, erythromycin, oxacillin, penicillin(16). buy STA-9090 Due to multi-drug resistance and the ability to PLX3397 acquire resistance to new antibiotics quickly, it is more and more difficult to treat S. aureus infection, especially with the emergence of vancomycin resistant S. aureus strains (7,8). As a result, many investigators resort to immunological approaches to contain S. aureus infection (9). Many components of S. aureus, such as capsular polysaccharide (9), poly-N-acetylglucosamine

(10), clumping factor A (11), clumping factor B (12), iron-regulated surface determinant (IsdB) (13) and fibronectin-binding protein (FnBP) (14), can generate immune responses that afford partial protection against S. aureus challenge in experiment animals. It is difficult to develop S. aureus vaccines because there are many pathogenic determinants in S. aureus and different clinical isolates may have different pathogenic determinants. Ideal vaccine candidates for S. aureus should be expressed broadly in different S. aureus

clinical isolates and be consistent among different strains. Vaccines consisting of several components may induce better protective immunity against infective selleck chemical S. aureus (15). In this study, to screen good vaccine candidates against S. aureus, a panel of pathogenic proteins of S. aureus was expressed and dot blotted with sera from mice infected with S. aureus USA300, 546 and 1884, respectively. The proteins that interact with the sera were selected to immunize BALB/c mice. The immunized mice were then challenged with S. aureus USA300. A protein named SasA was found to be able to induce protective immunity against lethal challenge of S. aureus USA300. Staphylococci were cultured on tryptic soy agar or in broth at 37 °C. S. aureus USA300 were obtained from ATCC. This strain does not produce toxic shock syndrome toxin. The lethal dosage of S. aureus USA300 or S. aureus 546 was determined before as in respectively. S. aureus 546 and S. aureus 1884 were obtained from China Veterinary Culture Collection Center (CVCC). E.

g. pathogenic) changes. Therefore, in addition to mitochondrial DNA, Y-chromosome, microsatellites, single nucleotide polymorphisms and other markers, immunogenetic polymorphisms represent

essential PF-2341066 and complementary tools for anthropological studies. More than a century has elapsed since the discovery of the ABO blood groups in 1900 by Karl Landsteiner through haemagglutination assays, (see ref. 1 for a review) an event that marked the starting point of immunogenetic studies applied to the analysis of genetic variation in humans. Other antigens of the red blood cells (together with allozymes, through electrophoretic techniques) were successively found and studied in human populations during the first half of the 20th century.2 Molecules that are instrumental in the immune responses of human beings also revealed inter-individual differences such as immunoglobulins, with the discovery of allotypic variation,3,4 and human leucocyte antigen (HLA) molecules,5 with the finding of an unexpectedly high degree of polymorphism at the level of their peptide-binding region (see http://www.ebi.ac.uk/imgt/hla/). Killer-cell immunoglobulin-like receptors (KIR) were also shown to exhibit a complex polymorphism where both the number of alleles and

EX 527 price the number of genes may vary among individuals.6 Today, almost 350 severe pathogens are registered on a worldwide scale (Gideon online. Retrieved from http://www.gideononline.com on 20 December 2010) and many others have existed and are now extinct. Each year, seasonal epidemics of influenza remind us that the turnover of most viruses is very rapid. A high level of polymorphism in the genes coding for molecules involved new in immune responses is therefore not surprising in light of our exposure to such a diversity of infectious agents, because we know that evolution may easily adapt the genetic pool of populations to specific environmental

pressures through natural selection. For example, red blood cell antigens were found to act as receptors for a number of pathogens, (e.g. Plasmodium vivax, for FY, Plasmodium falciparum, for GPA, Toxoplasma gondii, for RH), and hence to play an important role in the susceptibility or resistance of our organism against specific diseases. In the case of FY, the null allele was positively selected in some geographic regions, but not in others, allowing red blood cells to escape P. vivax infection.7 Also, HLA allelic variation may have been maintained through heterozygote advantage, because we know that some HLA alleles are associated with resistance to several fatal diseases, one recent example being the association of HLA-B*27, HLA-B*51 and HLA-B*57 with improved prognosis of AIDS.

Therefore, decreased leucocyte activation in infected CCR2−/− mice may explain the decreased cytokine storm and decreased tissue damage observed in these animals. The CCR4 receptor shown to be relevant for virus-induced liver damage and the associated

systemic inflammation in the present model. We also found that CCL17/TARC, one of the ligands for CCR4, was detectable at high levels in the spleen of infected mice. Viral load was not altered in CCR4−/− when compared with WT animals, which suggest that that CCR4 does not play a major role in the control of viral entry and replication, but contribute mostly to the cascade of events that lead to tissue and systemic damage. Interestingly, Ruxolitinib concentration CCR4 deficiency is associated with attenuated severity of murine polymicrobial sepsis and lipopolysaccharide-induced endotoxic shock, implicating Selleckchem Dabrafenib this receptor in the pathogenesis of acute conditions.[88, 89] Other experiments, however, have found a protective role for CCL22/MDC, a CCR4 ligand, in a caecal ligation and puncture model of sepsis in mice.[90] It is difficult to suggest the cellular and molecular mechanisms by which CCR4 may contribute to the pathogenesis of dengue. However, CCR4 may be important for the trafficking and activation

of NKT/invariant NKT (iNKT) cells and naive CD8+ cells by at least two independent chemokine pathways, including CCL17/TARC and CCL22.[91, 92] Moreover, pulmonary localization of iNKT cells is critical for the induction of airway hyperreactivity and requires CCR4 expression by iNKT cells.[93] In fact, excessive NKT/iNKT activation contributes to the pathogenesis of severe disease in our model.[70] Our studies suggest that the chemokine storm that follows severe primary DENV infection is associated with the development of inflammation rather than protection against severe disease. Hence, blockade of the chemokine system may be beneficial as co-adjuvant treatment for severe DENV infection and might be further explored. A summary of the role of CC chemokines and their receptors

in DENV infection is shown in Table 2. The NKT cells constitute a heterogeneous population of non-conventional Glycogen branching enzyme αβ T lymphocytes that recognize self and foreign (glyco) lipid antigens through their T-cell receptors (TCRs). NKT TCR-mediated responses are restricted by CD1d, a member of the non-polymorphic CD1 antigen-presenting protein family that promotes the presentation of endogenous and pathogen-derived lipid antigens to the TCR.[94-96] CD1d-restricted NKT cells are divided into invariant (iNKT cells, or type I NKT cells), the predominant subset which express an invariant TCR-α chain (Vα14Jα18 in mice), and variant (vNKT cells, or non-invariant or type II NKT cells), which express more diverse TCRs.[94, 95] Invariant NKT cells have regulatory functions in autoimmune and inflammatory diseases, cancer and infection.

2a). Mice receiving PBMC displayed a significant mononuclear cell infiltration, especially surrounding the hepatic ducts with endothelialitis (P < 0·0001) (Fig. 2a). MSC therapy on day 7 reduced liver pathology (P < 0·0086), with decreased cell infiltration and reduced endothelialitis selleck chemicals (Fig. 2a). Similarly, the small intestines of PBS-treated control mice appeared normal, with no sloughing of villi and no accumulation of infiltrating cells into the lamina propria (Fig. 2b). In comparison, NSG mice that received PBMC displayed blunting of villi with cell

infiltration into the lamina propria and intestinal crypts (Fig. 2b) (P < 0·0001). This was reduced significantly by human MSC therapy at day 7 (P < 0·0249). Control NSG mouse NU7441 lungs appeared normal, but PBMC delivery provoked cellular infiltration/inflammation (Fig. 2c) (P < 0·0002). In contrast to the protective effects in the liver and gut, treatment with MSC on day 7 did not ameliorate pathology in the lungs compared to aGVHD mice (Fig. 2c). Stimulation of MSC with proinflammatory cytokines such as IFN-γ promotes the immunosuppressive capacity in vitro and enhances their beneficial role in treating aGVHD in vivo [32, 36], a phenomenon termed ‘licensing’. Therefore, MSC were stimulated in vitro with IFN-γ (MSCγ) for 48 h prior to administration to NSG mice on day 0 in the aGVHD model. MSCγ therapy reduced aGVHD-related weight loss and pathology

(Fig. 1d,e), while significantly increasing the survival time of mice with aGVHD (P < 0·0015) in comparison to mice that had not received MSC therapy (Fig. 1f). MSCγ therapy on day 0 reduced aGVHD pathology of the liver significantly (P < 0·0163), reducing cell infiltration and endothelialitis (Fig. 2a). IFN-γ stimulated MSC also reduced gut pathology with reduced cell infiltration and significantly less tissue damage to villi (P < 0·0142) (Fig. 2b), similar in extent to non-stimulated L-gulonolactone oxidase MSC therapy at day 7. However, as seen earlier, MSCγ therapy did not ameliorate the pathology observed in the lung

(Fig. 2c). A simple explanation for the observation above could be that human MSC therapy reduces human PBMC engraftment in the NSG model. To exclude this possibility, the numbers of human CD45+ cells and the ratios of CD4/CD8 T cells were investigated in the above model. IFN-γ-stimulated human MSC therapy on day 0 or non-stimulated MSC therapy on day 7 did not affect the engraftment of human CD45+ cells (Fig. 3a). Human CD4 and CD8 T cells were detectable in the spleens of NSG mice following human PBMC infusion, but MSC therapy (IFN-γ-stimulated or not) did not prevent the engraftment of human T cells or significantly alter the CD4 : CD8 ratio (Fig. 3b). In support of this observation, the levels of human IL-2 in the sera of NSG mice following PBMC infusion was not significantly altered by MSC therapy (Fig. 3c), indicating that MSC therapy did not hinder effector cell engraftment.

All animal use was in accordance with the guidelines of the Animal Care and Use Committee of

the University of Massachusetts Medical see more School and The Jackson Laboratory and conformed to the recommendations in the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, National Research Council, National Academy of Sciences, 1996). Human PBMC were collected in heparin from healthy volunteers under signed informed consent in accordance with the Declaration of Helsinki and approval from the Institutional Review Board of the University of Massachusetts Medical School. Human fetal thymus and fetal liver (gestational age between 16 and 20 weeks) specimens were provided by Advanced Bioscience Resources (Alameda, CA, USA) or StemExpress (Placerville, CA, USA). Upon receipt, tissues were washed with RPMI supplemented with penicillin G (100 U/ml), streptomycin (100 mg/ml), fungizone (0·25 μg/ml) and gentamycin

(5 μg/ml) and then 1 mm3 fragments were prepared from the thymus and liver for transplantation. When indicated 1 mm3 fragments of fetal NSG mouse liver were co-implanted with the human tissues. The remaining human fetal liver was processed to recover human HSC as described below. Indicated groups of recipient mice were irradiated with 200 cGy and then implanted with a fetal thymus and fetal liver fragment together in the renal subcapsular space or subcutaneously in the ventral area. Following surgery, recipient mice received a subcutaneous injection of gentamycin (0·2 mg) and cefazolin (0·83 mg). selleck inhibitor To recover human HSC, fetal liver was minced and digested at 37°c for 20 min with a collagenase-dispase buffer (liver digest medium; Gibco, Carlsbad, CA, USA). The recovered cell suspension was then washed with RPMI supplemented with 10% fetal bovine serum (FBS)

and filtered through a metal sieve. Red blood cells were removed by Ficoll-Hypaque density centrifugation. The fetal BCKDHA liver cells were then depleted of CD3+ cells using a magnetic bead separation technique (Miltenyi Biotec, Inc., Auburn, CA, USA) and the percentage of CD34+ cells determined by flow cytometry. At a minimum of 4 h after irradiation of recipient mice, CD3-depleted fetal liver cells were injected i.v. with 1 to 5 × 105 CD34+ HSC per mouse. For analysis of human haematopoietic engraftment, monoclonal antibodies specific for mouse CD45 (30-F11), human CD45 (2D1), CD3 (UCHT1), CD4 (RPA-T4), CD8 (RPA-T8), CD10 (HI10A), CD11c (B-ly6), CD14 (HCD14), CD20 (2H7), CD27 (M-T271), CD33 (WM53), CD34 (581), CD38 (HIT2), CD45RA (HI100), CD123 (AC145) and IgD (IAG-2) were purchased from either BD Biosciences, Inc. (San Jose, CA, USA), eBiosciences (San Diego, CA, USA) or BioLegend (San Diego, CA, USA).

When Pax5 expression commits these progenitors to monopotent pre-B lymphocytes the two microRNAs (miRNAs) are downregulated. Upon transplantation, stem cells and progenitors can reside in the BM, while pre-B cells, after their commitment, no longer do so. Retrovirally transduced, doxycycline-induced overexpression of either miR-221 or miR-222 in pre-B-I cells does not revert their monopotency to multipotency. However, upon transplantation miR-221, but not miR-222, transduced pre-B-I cells regain the capacity to reside in the BM. Upon subsequent termination of miR-221-expression by removal of doxycycline,

the transplanted cells leave the BM again. Microarray analyses identified 25 downregulated miR-221-target genes, which GW 572016 could function to localize phases of B-lymphocyte development in BM before and after commitment.

MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression programs of multiple biological processes on posttranscriptional levels. miRNAs exert their functions Selleck Stem Cell Compound Library by binding to cognate mRNA sequences, often in the 3′ untranslated region (UTR), thereby promoting mRNA instability or repression of productive translation [1]. Deletion of the miRNA processing machinery results in early embryonic lethality and dicer-deficient embryonic stem cells are defective in differentiation [2, 3], highlighting the importance of miRNAs IKBKE in development. Differentiation stage-specific expression of miRNAs in the mammalian hematopoietic system has been described [4-9]. Only

in a few cases has it been possible to identify direct targets for the regulatory action of an miRNA [5]. Mature B lymphocytes develop from pluripotent hematopoietic stem cells (pHSCs), over multipotent myeloid/lymphoid progenitors (MPPs), to common lymphoid progenitors (CLPs), Pax5 then commits the development to pre-B-I cells, pre-B-cell receptor positive (preBCR+) pre-B-II cells, and sIgM+ immature B cells [10, 11]. Consequently, Pax5-deficiency blocks B-cell development at an multipotent CLP-like, CD19− cell stage [12, 13]. CD19+Pax5+/+ pre-B-I cells [14] from fetal liver, but not from BM [15] and from CD19−Pax5−/− multipotent/CLP-like pro/pre-B cells [16, 17] can be established on stromal cells and with IL-7 as long-term-proliferating cell lines. Pax5+/+ pre-B-I cells can differentiate into B cells both in vitro as well as after transplantation in vivo. However, Pax5−/− multipotent CLP-like pro/pre-B cells, blocked in B-cell development, can be induced in the proper cytokine/stromal cell environment in vitro, as well as after transplantation in vivo to T cells, NK cells, and, although at lower efficiencies, to myeloid and erythroid cells.