Short-term changes in frequencies of circulating leukocytes associated with narrowband UVB phototherapy in people with clinically isolated syndrome.

Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). Low environmental exposure to UV radiation is implicated in risk of developing MS, and therefore, narrowband UVB phototherapy might delay progression to MS in people with CIS. Twenty individuals with CIS were recruited, and half were randomised to receive 24 sessions of narrowband UVB phototherapy over a period of 8 weeks. Here, the effects of narrowband UVB phototherapy on the frequencies of circulating immune cells and immunoglobulin levels after phototherapy are reported. Peripheral blood samples for all participants were collected at baseline, and 1, 2, 3, 6 and 12 months after enrolment. An extensive panel of leukocyte populations, including subsets of T cells, B cells, monocytes, dendritic cells, and natural killer cells were examined in phototherapy-treated and control participants, and immunoglobulin levels measured in serum. There were significant short-term increases in the frequency of naïve B cells, intermediate monocytes, and fraction III FoxP3+ T regulatory cells, and decreases in switched memory B cells and classical monocytes in phototherapy-treated individuals. Since B cells are increasingly targeted by MS therapies, the effects of narrowband UVB phototherapy in people with MS should be investigated further.

Blinatumomab for the Treatment of Philadelphia Chromosome-Negative, Precursor B-cell Acute Lymphoblastic Leukemia.

Blinatumomab is a CD19/CD3 bispescific antibody designed to redirect T cells toward malignant B cells and induce their lysis. It recently gained accelerated approval by the FDA for the treatment of relapsed or refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (RR-ALL). In the phase II trial that served as the basis for approval, blinatumomab demonstrated significant single-agent activity and induced remission [complete remission (CR) and CR with incomplete recovery of peripheral blood counts (CRh)] in 43% of 189 adult patients with RR-ALL; the majority of responders (82%) also attained negative minimal residual disease (MRD(-)) status that did not generally translate into long-term remissions in most cases. Additional studies show that blinatumomab can induce high response rates associated with lasting remissions in patients in first remission treated for MRD positivity, suggesting a role for blinatumomab in the upfront, MRD-positive setting. Blinatumomab infusion follows a predictable immunopharmacologic profile, including early cytokine release that can be associated with a clinical syndrome, T-cell expansion, and B-cell depletion. Neurologic toxicities represent a unique toxicity that shares similarities with adverse effects of other T-cell engaging therapies. Further studies are needed to clarify the optimal disease setting and timing for blinatumomab therapy. Additional insights into the pathogenesis, risk factors, and prevention of neurologic toxicities as well as a better understanding of the clinical consequences and biologic pathways that are associated with drug resistance are needed.

B cells as a therapeutic target for IFN-ß in relapsing-remitting multiple sclerosis.

IFN-ß-1b is a first-line immunomodulatory therapy for relapsing-remitting multiple sclerosis (RR MS). However, its effects on B cells have not been characterized. In vitro studies of B cells derived from RR MS patients revealed that IFN-ß-1b decreases B cells' stimulatory capacity, as detected by inhibition of the Ag-specific T cell proliferative response upon Ag presentation by IFN-ß-1b-treated B cells. Our study has identified that IFN-ß-1b inhibited B cells' stimulatory capacity in RR MS patients and healthy controls through the suppression of CD40 and CD80 expression, whereas the MHC class I and II expression was not changed. IFN-ß-1b in vitro treatment inhibited B cell secretion of IL-1ß and IL-23 and induced IL-12 and IL-27. Supernatants transferred from IFN-ß-1b-treated B cells inhibited Th17 cell differentiation, as they suppressed gene expression of the retinoic acid-related orphan nuclear hormone receptor C and IL-17A and secretion of IL-17A. In addition, IFN-ß-1b induced B cells' IL-10 secretion, which may mediate their regulatory effect. Studies of B cells derived from RR MS patients treated with recombinant s.c. injected IFN-ß-1b revealed that they induced a significantly lower proliferative response in allogenic MLR than the B cells from untreated patients. Further confirming the IFN-ß-1b in vitro-induced changes in B cell cytokine secretion, B cells derived from the IFN-ß-1b-treated patients secreted significantly lower levels of IL-1ß and IL-23 and higher levels of IL-12 and IL-27 in comparison with the B cells derived from untreated patients. We conclude that IFN-ß-1b exerts its therapeutic effects in part by targeting B cells' functions that contribute to the autoimmune pathogenesis of RR MS.

IL-9-induced expansion of B-1b cells restores numbers but not function of B-1 lymphocytes in xid mice.

Mice expressing the X-linked immunodeficiency (xid) mutation lack functional Bruton's tyrosine kinase and were shown to be specifically deficient in peritoneal B-1 lymphocytes. We have previously shown that IL-9, a cytokine produced by TH2 lymphocytes, promotes B-1 cell expansion in vivo. To determine whether IL-9 overexpression might compensate the xid mutation for B-1 lymphocyte development, we crossed xid mice with IL-9-transgenic mice. In this model, IL-9 restored normal numbers of mature peritoneal B-1 cells that all belonged to the CD5(-) B-1b subset. Despite this normal B-1 lymphocyte number, IL-9 failed to restore classical functions of B-1 cells, namely, the production of natural IgM Abs, the T15 Id Ab response to phosphorylcholine immunization, and the antipolysaccharide humoral response against Streptococcus pneumoniae. By using bromelain-treated RBC, we showed that the antigenic repertoire of these IL-9-induced B-1b lymphocytes was different from the repertoire of classical CD5(+) B-1a cells, indicating that the lack of B-1 function by B-1b cells is associated with distinct Ag specificities. Taken together, our data show that B-1b cell development can restore the peritoneal B-1 population in xid mice but that these B-1b cells are functionally distinct from CD5(+) B-1a lymphocytes.

Deletion of the DQ52 element within the Ig heavy chain locus leads to a selective reduction in VDJ recombination and altered D gene usage.

The process of V(D)J recombination that leads to the assembly of Ig gene segments is tightly controlled during B cell differentiation. Two germline transcripts, one of which (mu(0)) originates from the promoter region of DQ52, may control the accessibility of the heavy chain locus. Here, we present the analysis of a mouse line in which the DQ52 gene together with its regulatory sequences is deleted by a Cre/loxP-based strategy. In F(1) (DQ52(+/-)) mice, the use of the JH3 and JH4 elements in DJ or VDJ junctions of the DQ52(-) allele was strongly reduced in both the bone marrow pre-B and spleen cells, while the JH1 and JH2 elements were used with normal frequencies. In addition, IgM(+) B cells of bone marrow and spleen used the DQ52(-) allele less frequently. On DJ joints of the DQ52(-) allele, there was 2 times less processing of JH3 ends, which resulted in clearly increased addition of P nucleotides. Although the use of D elements in DJ joints was quite similar, an altered D repertoire was found in VDJ joints of the DQ52(-) allele. In splenic B cells of the DQ52(-/-) mouse the amino acid distribution of the CDR3 was skewed, probably to compensate for the altered processing of JH3 ends. Thus, we have shown an interesting selective effect of the DQ52 region on controlling accessibility to 3' JH elements on the Ig locus, which also seems to influence the processing of DJ joints. We propose a model in which the DQ52 promoter region enhances the induction of secondary DJ rearrangements.

[Clinical study in treating intractable ulcerative colitis with traditional Chinese medicine].

UNLABELLED: Clinical double blind study in treating 153 intractable ulcerative colitis with Chinese medicinal herbs was conducted, the patients were randomly assigned to three groups. Group I is administered with Jian Pi Ling (JPL) tablet with retention-enema of Radix Sophorae Flavescentis and Flos Sophora (RSF-FS) decoction per night, group II with salicylazosulfapyridine (SASP) and retention-enema of dexamethasone, group III with placebo and retention-enema of decoction as that in group I. After 90 days every patients were checked by means of fibro-enteroscope, pathologic and immunologic parameters. THE RESULTS: the curative rates of group I, II, III, were 53.1%, 27.7% and 19.0%, the total effective rates were 85.9%, 59.6% and 45.2% respectively. By comparison among groups, the efficacy of group I was the best (P < 0.01). The check of T and B lymphocyte subpopulation showed the B lymphocyte of group I markedly decreased, OKT3 and OKT8 obviously increased, the ratio of OKT4 and OKT8 approached normal value. The amount of IgG, IgM, C3 increased abnormally, decreased dramatically after medication, while those of group II and III have not changed significantly. The bacteriostatic test in vitro showed the bacteriostatic effect of RSF-FS on pathogenic B. coli, Shigella dysenteriae and Staphylococcus aureus was the best, that of solution Jian Pi Ling the next, that of SASP was the least effective. Therefore, the principle and method of group I seems to be the best therapeutic programme.

Immunohistochemical analysis of lymphocytes in postmortem study of the heart from fatal cases of the eosinophilia myalgia syndrome and of the toxic oil syndrome.

Inflammatory lesions of coronary arteries and cardiac neural structures are postmortem histopathologic features of both the eosinophilia-myalgia syndrome (EMS) and the toxic oil syndrome (TOS). The inflammation is primarily lymphocytic. For further definition of the lymphocytes, immunohistochemical analysis was carried out in the hearts of three victims of EMS and four victims of TOS. Many CD45RO+ T cells, OPD4+ helper/inducer T (Th) cells, and CD20+ B cells were observed in these neurovascular lesions, notably in the conduction system and the coronary chemoreceptor. T cells were prominent in EMS around nerves, ganglia, and sometimes around arteries. B cells and Th cells, however, were more prominent in TOS around arteries. The percentage of T cells in EMS (59.6 +/- 2.4%) was significantly higher than in TOS (45.0 +/- 4.2%), whereas that of B cells was significantly higher in TOS (27.7 +/- 4.4%) than in EMS (17.5 +/- 1.3%) (p < 0.01, respectively). There was no significant difference between the syndromes in the percentages of Th cells. Therefore cytotoxic/suppressor T cells are more prominent in EMS than in TOS. These findings suggest that (1) cellular immune mechanisms are involved in cardioneuropathy in victims of both EMS and TOS; (2) cell-mediated cytotoxicity directed against chemoreceptor neural structures and sinus nodal myocytes is prominent in EMS; and (3) some humoral factors may also be involved in the pathogenesis of TOS.

Immune reconstitution following peripheral blood stem cell transplantation, autologous bone marrow transplantation and allogeneic bone marrow transplantation.

The rate and pattern of recovery of total lymphocytes, T cell subsets, B cells and NK cells were compared for 12 months following recovery phase peripheral blood stem cell (PBSC) autotransplantation (n = 49), autologous (n = 7) and allogeneic BMT (n = 11). The PBSC group had a significantly faster recovery of total lymphocyte count, total T cells (CD3+ cells), CD8 cells and CD4 cells than the allogeneic BMT group. The pattern of earlier recovery of CD8 cells than CD4 cells was the same for each type of transplant. Reconstitution following autologous BMT was intermediate between PBSC and allogeneic BMT. Multivariate analysis identified type of transplant, number of mononuclear cells transplanted and conditioning regimen as significantly influencing immune recovery.