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S A Brod

Publications and source records attributed to S A Brod.

36 records · Page 2Linked to original sources
PubMed1995

Oral administration of human or murine interferon alpha suppresses relapses and modifies adoptive transfer in experimental autoimmune encephalomyelitis.

Chronic relapsing experimental autoimmune encephalitis (CR-EAE) is an inflammatory process of the central nervous system (CNS) that closely resembles the human disease multiple sclerosis (MS). EAE was induced in SJL/J mice and following recovery from the initial attack, animals were fed varying doses of human or murine interferon alpha (IFN-alpha), or mock IFN three times per week. After relapse, concanavalin A-activated spleen cells were transferred adoptively from orally fed animals into recipient animals. Oral administration of human or murine IFN-alpha suppressed relapse in actively immunized animals, modified adoptive transfer of EAE, and decreased mitogen/antigen proliferation and IFN-gamma secretion in both donors and recipients. IFN-alpha acts orally by modifying the encephalitogenicity of donor spleen T cells.

Administration, Oral↗
PubMed1995

Modification of acute experimental autoimmune encephalomyelitis in the Lewis rat by oral administration of type 1 interferons.

The effect of orally administered type 1 interferons on the severity of acute experimental autoimmune encephalomyelitis (EAE), a T cell-mediated autoimmune disease, was examined by inoculation of Lewis rats with guinea pig myelin basic protein (GPMBP) and complete Freund's adjuvant. Rats were fed either rat species-specific or human recombinant type 1 interferon (IFN) or mock IFN daily for 7 days preceding immunization and for 21 days thereafter. There was a significant decrease in the clinical score and inflammatory foci in animals fed 5000 units IFN compared with mock-treated animals. There was a significant decrease in clinical score and number of inflammatory foci in spinal cord in animals fed orally 5000 units human recombinant IFN-alpha PO compared with SC 5000 units recombinant human IFN-alpha. Oral administration of type 1 interferon, as opposed to subcutaneous administration, inhibited the secretion of IFN-gamma from ConA-activated draining popliteal lymph node cells compared with mock-fed animals. These experiments demonstrate that acute EAE is more effectively inhibited by equivalent amounts of orally in contrast to parenterally administered IFN-alpha. These results suggest that type 1 IFNs are active by the oral route and have significant clinical and histologic effects in acute autoimmune disease.

Administration, Oral↗
PubMed1994

Suppression of relapsing experimental autoimmune encephalomyelitis in the SJL/J mouse by oral administration of type I interferons.

We induced a chronic relapsing form of experimental autoimmune encephalomyelitis in 7- to 10-week-old female SJL/J mice using a subcutaneous injection of an emulsion containing syngeneic mouse spinal cord homogenate in phosphate-buffered saline and Mycobacterium tuberculosis (MT) in incomplete Freund's adjuvant. Following the animals' recovery from the first attack periods, we fed them varying doses of type I interferon (IFN) or mock IFN three times per week for 6 weeks. This treatment decreased proliferation to guinea pig myelin basic protein and MT compared with control in draining lymph node and diminished inflammation in the CNS. Oral IFN altered the cytokine profile of concanavalin A-activated spleen cells by decreasing IFN-gamma secretion. These results suggest that type I IFNs are active by the oral route, have significant clinical and immunomodulatory effects, and can decrease an established and ongoing immune response to sensitized antigens. The oral administration of biologic-response modifiers, such as type I IFNs, provides a potentially nontoxic, convenient, continuous means of delivering immunoactive substances via the gut regional immune system that can alter cytokine production and suppress clinical relapses.

Administration, Oral↗
PubMed1994

Defective CD3 mediated proliferation and LPS responsiveness in multiple sclerosis.

Multiple sclerosis [MS] is a chronic inflammatory disease of the central nervous system which has been postulated to be a T cell mediated disease. We examined proliferation of mononuclear cells to OKT3 mAb, Con A, ionomycin plus PMA and human myelin basic protein in subjects with relapsing-remitting and chronic progressive multiple sclerosis. Age and sex matched controls demonstrated a good proliferation to anti-CD3 mAb whereas subjects with relapsing-remitting multiple sclerosis showed a significantly decreased anti-CD3 mAb response. There was no difference in mitogen, ionomycin plus PMA or human MBP proliferation between controls and MS subjects. There was also a trend for decreasing anti-CD3 mAb proliferation in patients with chronic progressive multiple sclerosis compared to controls. LPS significantly decreased anti-CD3 mAb proliferation in controls but not in the MS subjects. An abnormality of signal transduction via the CD3 T-cell receptor complex in T cells and responsiveness to the immunomodulatory effect of IFN inducers may exist in multiple sclerosis.

CD3 Complex↗
PubMed1992

CTLA-4 and CD28 mRNA are coexpressed in most T cells after activation. Expression of CTLA-4 and CD28 mRNA does not correlate with the pattern of lymphokine production.

Ag-presenting cells provide at least two distinct signals for T cell activation. T cell receptor-dependent stimulation is provided by presentation of a specific peptide Ag in association with MHC molecules. In addition, APC also supply costimulatory signals required for T cell activation that are neither Ag- nor MHC restricted. One such costimulatory signal is mediated via the interaction of B7 on APC with the CD28 receptor on T cells. Recently, CTLA-4 has been shown to be a second B7 receptor on T cells. In the present report, we have examined the expression of CD28 and CTLA-4 on a panel of resting and activated normal T cell subsets and T cell clones by RNA blot analysis in an attempt to determine whether their expression defines reciprocal or overlapping subsets. CD28 was detected in resting T cells, whereas CTLA-4 was not. After stimulation with PHA and PMA for 24 h, CTLA-4 mRNA was expressed in both the CD4+ and CD8+ subsets as well as in CD28+ T cells. We examined 37 human and six murine T cell clones that had been previously characterized for their cytokine production. After activation, CTLA-4 and CD28 mRNA were coexpressed in 36 of 37 human T cell clones and all six murine T cell clones. These included T cells of CD4+8-, CD4-8+, and CD4-8- phenotypes as well as clones with Th1 and Th2 cytokine profiles. In contrast, CD28 but not CTLA-4 mRNA was detected in leukemic T cell lines and myelomas. CTLA-4 and B7 mRNA but not CD28 mRNA was detected in two long term HTLV-I-transformed T cell lines. These data demonstrate that CD28 and CTLA-4 mRNA are coexpressed in most activated T cells and T cell clones, providing evidence that they do not define reciprocal subsets. Moreover, they are consistent with the hypothesis that B7 transmits its signal through a single receptor, CD28, on resting T cells, and multiple receptors, CD28 and CTLA-4, on activated T cells.

Abatacept↗
PubMed1991

Restricted T cell expression of IL-2/IFN-gamma mRNA in human inflammatory disease.

It has been difficult to demonstrate functionally distinct T cell populations in humans on the basis of cytokine secretion. As previous investigators have examined the T cell cytokine profile from immunized animals, we examined whether Th1 or Th2 type T cells could be identified in the peripheral blood or cerebrospinal fluid (CSF) immune compartments from subjects with or without inflammatory diseases. Using limiting dilution analysis and growth with PHA and IL-2/IL-4, we directly cloned a total of 177 T cells from the peripheral blood and CSF of seven subjects, four with inflammatory disease and three control subjects, and examined the cytokine message profile after stimulation with ionomycin and PMA. We found that most clones from both the peripheral blood and CSF express IL-1, IL-2, IL-4, IFN-gamma, or TNF-alpha cytokine mRNA after activation with ionomycin and PMA. All T cell clones tested produced TNF-alpha mRNA, and all but 14 produced IFN-gamma mRNA. As reported previously, Th0 cells, which produced IFN-gamma, IL-2, IL-4, and IL-5 mRNA, were found in most subjects. In striking contrast, Th1 cells, which expressed IL-2 and IFN-gamma but not IL-4 or IL-5 mRNA, were present in both peripheral blood and CSF of subjects with inflammatory disease but not found in peripheral blood or CSF of subjects without systemic inflammation. Th2 cells, expressing IL-4 and IL-5 but not IFN-gamma or IL-2 mRNA, were not found in any subject. These data present the first evidence for Th1 T cell clones in humans that may be associated with systemic inflammation.

Antigens, CD↗
PubMed1991

Common T-cell receptor V beta usage in oligoclonal T lymphocytes derived from cerebrospinal fluid and blood of patients with multiple sclerosis.

T-cell populations were investigated in the blood and cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases. Individual T cells were directly cloned from the cerebrospinal fluid and blood before in vitro expansion, and their clonotypes were compared by Southern blot analysis of the rearrangement patterns of their T-cell receptor beta chain and gamma chain genes. This allowed the determination of whether two T cell clones shared the same T-cell receptor and thus arose from identical, clonally expanded (oligoclonal) progenitor T cells. As an extension of previous studies, oligoclonal T-cell clones were identified in both cerebrospinal fluid and blood populations in 5 of 9 patients with inflammatory demyelinating disease among a total of 486 blood and cerebrospinal fluid T-cell clones. In contrast, no clonally expanded T-cell populations were found among a total of 424 clones derived from either blood of 4 normal control subjects or blood and cerebrospinal fluid of 8 patients with other neurological diseases. Analysis of T-cell receptor V beta genes among 4 oligoclonal T-cell populations derived from 3 patients with multiple sclerosis demonstrated common usage of the V beta 12 gene segment. These data suggest that oligoclonal T cells share similar specificities and that clonal expansion may have resulted from specific stimulation by an antigen. Moreover, identical clones between blood and cerebrospinal fluid were observed in 3 of 9 patients with demyelinating disease, thus providing further evidence of an equilibrium between peripheral and central nervous system immune compartments.

Adolescent↗
PubMed1991

Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin antigens: IV. Suppression of chronic relapsing disease in the Lewis rat and strain 13 guinea pig.

Oral administration of proteins is a long-recognized method of inducing antigen-specific peripheral immune tolerance. We previously showed that oral administration of myelin basic protein suppresses monophasic experimental autoimmune encephalomyelitis in the Lewis rat when it is given in association with immunization and prior to disease onset. As a potential therapy for human autoimmune disease, it is crucial to determine whether oral tolerance can ameliorate an ongoing immune response. We therefore asked whether oral administration of myelin antigens, after sensitization and disease expression has occurred, could affect immunological, clinical, or pathological features of experimental autoimmune encephalomyelitis. Chronic relapsing experimental autoimmune encephalomyelitis was induced in the Lewis rat and strain 13 guinea pig by immunization with whole guinea pig cord homogenate, complete Freund's adjuvant, and Mycobacterium tuberculosis. Following recovery from the first attack, animals were orally given bovine myelin, guinea pig myelin, or guinea pig myelin basic protein three times per week for up to 3 months. Animals receiving myelin products orally had decreased severity and frequency of clinical relapses, decreased delayed-type hypersensitivity responses to myelin antigens, diminished inflammation in the central nervous system (CNS), and decreased areas of CNS demyelination. In the rat, guinea pig myelin basic protein was as effective as guinea pig myelin in ameliorating the disease and also resulted in decreased serum anti-myelin basic protein antibody levels. No exacerbation of disease or worsening of pathological findings occurred in the animals given myelin products. These results demonstrate that oral administration of myelin antigens can suppress chronic relapsing experimental autoimmune encephalomyelitis and have direct relevance to therapy of human demyelinating disorders such as multiple sclerosis.

Administration, Oral↗
PubMed1990

T-T cell interactions are mediated by adhesion molecules.

The mechanism by which T cells signal other T cells is not well defined. This was investigated by studying the ability of circulating T cells to induce the proliferation of autologous T cell clones. Peripheral blood T cells activated by cross-linking of the CD3/T cell receptor complex, which increased the expression of cell adhesion molecules LFA-1, LFA-3 and ICAM-1, induced the proliferation of autologous T cell clones. Irradiated antigen-activated peripheral blood T cells could also induce the proliferation of T cell clones which could not recognize that antigen. T-T cell activation required cell contact, was not major histocompatibility complex (MHC) restricted and was blocked by monoclonal antibodies directed against adhesion molecules CD2 and LFA-3 but was not blocked by antibody to class II MHC determinants. As CD2 is the natural ligand for LFA-3, increased expression of T cell surface adhesion molecules LFA-1, ICAM-1 and particularly LFA-3 during an inflammatory response may rapidly recruit T cells that are activated through the CD2 pathway. These results allow a simplified model to explain how relatively few antigen/MHC-specific T cells can recruit large numbers of non-antigen-specific T cells in the generation of an inflammatory response and postulates a novel role of the CD2 molecule in T cell immune function.

Antibodies, Monoclonal↗
PubMed1990

Frequency analysis of CD4+CD8+ T cells cloned with IL-4.

The coexpression of both CD4 and CD8 molecules on T cells occurs in the peripheral blood at a low frequency and can be generated transiently on CD4+ peripheral blood T cells by treatment with lectin which induces CD8 biosynthesis and cell surface expression. We have cloned T cells in a nonselective fashion from normal subjects in the presence of either IL-2, rIL-4 and IL-2, or rIL-4 and have examined the phenotypic expression of CD4 and CD8. The addition of excess rIL-4 increased the expression of CD8 on the surface of CD4+ T cell clones but did not increase CD4 expression on CD8+ T cell clones. There were three patterns of CD4 and CD8 expression observed: high density CD8 with no CD4 expression; high density CD4 with low CD8 expression; or high density CD4 with higher cell surface CD8 expression which was regulated by the presence of rIL-4. CD4+ T cell clones originally cultured in IL-2 and rIL-4 and subsequently grown in IL-2 alone exhibited decreased expression of the CD8 molecule. The increased expression of CD8 did not correlate with NK activity or lectin-dependent cytotoxicity in an antigen independent system. In addition, rIL-4 alone or in combination with IL-2 appeared to accelerate the growth curve of T cell clones as compared to IL-2 alone. These results show that IL-4 can upregulate CD8 expression on CD4+ T cell clones while not effecting CD4 expression on CD8+ T cell clones. As class I MHC is the ligand for the CD8 molecule, expression of CD8 induced by IL-4 on CD4+ T cells may allow for increased nonspecific cell to cell contact during the course of an inflammatory response.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1989

Lymphokine regulation of CD45R expression on human T cell clones.

Whether the expression of higher molecular weight isoforms of the T-200 complex represents different lineages of T cells and/or a sequential stage of the differential pathway of T cells has been unclear. Understanding T cell expression of higher molecular weight isoforms of the T-200 complex (CD45R) may be important because of their association with regulation of immune responses. By direct single cell cloning, we observed a number of long-term T cell clones that expressed CD45RA (2H4). CD45RA expression could be further regulated by ionomycin or the cytokines IL-1 and IL-6, but not IL-2, IL-4, or IFN-gamma. These results indicate that CD45RA expression may define T cell lineages of activated T cells partially controlled by the cytokines IL-1 and IL-6. Further, these results may associate regulatory actions of IL-1 and IL-6 with their ability to increase CD45RA expression in subpopulations of human T cells.

Antigens, Differentiation↗
PubMedDate not supplied

Predictors of success for drug discontinuation following neonatal seizures.

Guidelines for the discontinuation of antiepileptic drugs in neonatal seizures are not well defined. Some studies suggested possible criteria for antiepileptic drug discontinuation but no precise criteria have emerged. We performed a retrospective analysis of 58 infants with neonatal seizures during a 3 year period. Antiepileptic drugs were discontinued when patients were seizure-free for 3 months, had normal electroencephalography initially or at subsequent examination, and had a nonfocal examination. Normal initial electroencephalography was demonstrated to be a reliable predictor for discontinuing antiepileptic drugs successfully in 18 of 22 term infants; normal subsequent electroencephalography was a reliable predictor of successful discontinuation of antiepileptic drugs in 9 of 10 premature infants.

Anticonvulsants↗
PubMedDate not supplied

Adoptive transfer from interferon-alpha-fed mice is associated with inhibition of active experimental autoimmune encephalomyelitis by decreasing recipient tumor necrosis factor-alpha secretion.

Ingested type I interferon (IFN) suppresses clinical relapse in murine chronic experimental autoimmune encephalomyelitis (EAE), inhibits clinical attacks more effectively than subcutaneous doses, and decreases the adoptive transfer of EAE. To determine whether splenocytes from IFN-fed donors were "suppressor-like" populations, donor SJL/J mice were immunized and fed with mock IFN-alpha or with IFN-alpha every other day for at least 4 weeks after initial clinical attack. Recipients of adoptively transferred CD8+ T cells from mock IFN-alpha-fed donors showed no clinical improvement of clinical disease compared with actively immunized controls. In contrast, recipients of adoptively transferred CD8+ T cells from IFN-alpha-fed donors showed decreased clinical disease compared with recipients of mock IFN-alpha-fed CD8+ T cells. To evaluate the mechanism of protection by donor CD8+ T cells and to determine if ingested IFN-alpha activates natural immunomodulatory cell populations, the authors used the acute EAE model and naïve-fed donor animals as sources of T cells and CD8+ T cells. Con A-activated spleen T cells from naïve nonimmunized mock IFN-alpha-fed donors inhibited actively induced disease and showed decreased recipient TNF-alpha secretion compared with recipients of T cells from mock IFN-fed mice. Donor activated spleen CD8+ T cells from naïve nonimmunized IFN-alpha-fed animals suppressed actively induced EAE in recipients and showed decreased IFN-gamma and TNF-alpha proinflammatory secretion. Decreased recipient TNF-alpha secretion correlates best with the disease protection from IFN-fed T and CD8+ T cells.

Administration, Oral↗