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S A Brod

Publications and source records attributed to S A Brod.

At least 19 recordsLinked to original sources
PubMed2000

Ingested interferon-alpha prevents allograft islet transplant rejection.

BACKGROUND: Ingested interferon (IFN)-alpha is a biological response modifier in experimental autoimmune encephalomyelitis and multiple sclerosis, and prevents type 1 diabetes in nonobese diabetic mice. Islet transplantation possesses significant potential advantages over whole-gland transplantation because it is simple, may achieve insulin independence, and has clear advantages over exogenous insulin therapy. Therefore, we examined whether ingested IFN-alpha, administered to islet allograft recipients, could prevent islet allograft rejection. METHODS: Recipient C3H mice (H2k) were made diabetic and either untreated or treated with 10-1000 international units (IU) of ingested murine IFN-alpha daily from day -7 through day +14 after transplantation for a total of 21 days. Seven days after diabetes induction, recipients received allograft islets isolated from C57BL.10 donors (H2b) under the kidney capsule and were followed for overt diabetes via elevated blood glucose. RESULTS: Control recipients and recipients fed 1000 IU all became diabetic by day 13, whereas mice ingesting IFN-alpha had delayed rejection for up to 27 (10 IU) to 29 days (100 IU) after islet transplantation. Treatment of recipients of islet allografts with ingested IFN-alpha doubles the time period before rejection compared with control mice. The feeding period with daily IFN-alpha was doubled from 21 days to 42 days in total, 7 days before transplantation and 35 days after transplantation. CONCLUSION: Treatment of recipients of islet allografts with prolonged ingested IFN-alpha prevents rejection in a subset of recipients. Ingested IFN-alpha may prevent rejection if given continuously after transplantation.

Administration, Oral↗
PubMed2000

Combination therapy with glatiramer acetate (copolymer-1) and a type I interferon (IFN-alpha) does not improve experimental autoimmune encephalomyelitis.

We sought to determine whether combinations of glatiramer acetate and parenteral or ingested type I interferon were synergistic in experimental autoimmune encephalomyelitis. Glatiramer acetate, subcutaneous murine interferon-alpha, or ingested murine interferon-alpha individually improved clinical scores. In contrast, glatiramer acetate in conjunction with either subcutaneous or ingested interferon-alpha did not improve clinical scores compared with control. These data suggest that clinical trials designed to test a possible synergistic effect of glatiramer acetate and type I interferon in humans should be designed to detect possible adverse effects of this combination of immunomodulatory agents.

Animals↗
PubMed1999

Ingested interferon alpha induces Mx mRNA.

We have demonstrated that ingested murine interferon alpha (IFN-alpha) suppressed clinical relapse in chronic relapsing experimental autoimmune encephalomyelitis (CR-EAE), decreased inflammation and suppressed the adoptive transfer of EAE, and is a biological response modifier in patients with multiple sclerosis. We examined the relative levels of the Mx mRNA signal using semiquantitative reverse transcription-polymerase chain reaction analysis on splenocytes from mice and peripheral blood mononuclear cells from man after IFN-alpha ingestion. Both mice and man demonstrated inducible levels of Mx mRNA after ingesting IFN-alpha. Murine spleen T cells and CD8(+)T cells also demonstrated upregulation of Mx mRNA. Murine whole splenocytes demonstrated upregulation of Mx mRNA after IFN-alpha ingestion of 10 and 100 U, but not after 0, 1000, 5000 U. Ingested IFN-alpha acts via established pathways of type 1 IFN signalling.

Administration, Oral↗
PubMed1999

Autoimmunity is a type I interferon-deficiency syndrome corrected by ingested type I IFN via the GALT system.

Type I interferons (IFN-alpha/beta), products of the innate immune system, can modulate immune function whereas proinflammatory IFN-gamma (type II IFN), a product of the acquired immune system upregulates inflammation and enhances cell mediated immunity. We have proposed a unifying hypothesis of the origin of autoimmunity as a type I IFN immunodeficiency syndrome involving inadequate regulation of the acquired immune system product IFN-gamma by the IFN-alpha/beta innate immune system. The common theme of ingested type I IFNs in autoimmunity is inhibition of proinflammatory type II IFN systemically or at the target organ. In multiple sclerosis (MS) and insulin-dependent diabetes mellitus (IDDM) at the target organ, and in rheumatoid arthritis (RA) as a regulator of other proinflammatory cytokines, IFN-gamma is the nexus of inflammation in autoimmunity. Ingested type I IFNs counteract type II IFN, overcome the relative lack of type I IFN activity, and ameliorate autoimmunity. The administration of type I IFNs (IFN-alpha/beta) via the gut offers an exciting alternative to systemic application for overcoming the type I IFN immunodeficiency in autoimmunity. Successful use of ingested type I IFN in three separate prototypical autoimmune diseases suggests a broad antiinflammatory therapeutic profile for this technology.

Administration, Oral↗
PubMed1998

Ingested interferon alpha suppresses type I diabetes in non-obese diabetic mice.

Type I diabetes mellitus is a chronic disorder that results from autoimmune destruction of the insulin-producing pancreatic beta cell. The non-obese diabetic mouse is a model of the human autoimmune disease Type I diabetes [1-3]. We have previously shown that ingested type 1 interferon inhibits chronic relapsing experimental autoimmune encephalomyelitis and the adoptive transfer of experimental autoimmune encephalomyelites by T cells, and decreases both antigen-specific and mitogen-induced pro-inflammatory cytokine secretion in this disorder. We therefore tried to determine whether ingested murine interferon alpha inhibits insulinitis and suppresses Type I diabetes mellitus in non-obese diabetic mice. Murine interferon alpha, given daily, decreased islet inflammation and suppressed diabetes. It increased the concanavalin A and ionomycin plus myristic acid palmitic ester-induced production of interleukin 4 and 10 and interferon gamma-secretion in spleen cells from treated mice. Adoptive transfer of unstimulated splenocytes secreting interleukin 4 and interleukin 10 from fed interferon alpha donors suppressed spontaneous diabetes mellitus in recipients. The protective effect of adoptively transferred unstimulated splenocytes shows the presence of ingested interferon alpha-activated regulatory splenic cell populations that may work via increased interleukin 4 or interleukin 10 production. Ingested interferon alpha administered during vulnerable periods in at-risk populations may potentially provide a continuous, convenient, non-toxic and effective treatment for Type I diabetes.

Adoptive Transfer↗
PubMed1997

Gut response. Therapy with ingested immunomodulatory proteins.

The recent negative results of the 2-year phase III trial of enteral myelin (Myloral), a preparation of bovine myelin given orally in multiple sclerosis (MS), warn that the efficacy of oral tolerization (ie, inducing hyporesponsiveness to a specific autoantigen) and the attractiveness of oral desensitization in animal models of MS may not translate into clinical practice. However, such failure should not deter further examination of the mouth, an immunologically interesting and patient-friendly route for immunomodulatory proteins.

Adjuvants, Immunologic↗
PubMed1997

Ingested IFN-alpha has biological effects in humans with relapsing-remitting multiple sclerosis.

Parenterally administered human recombinant type I interferons (hrIFN) in relapsing-remitting multiple sclerosis (RRMS) decrease relapses and spontaneous in vitro IFN-gamma production, reduce clinical progression, and decrease magnetic resonance imaging (MRI)-defined disease activity and lesions. Parenterally administered type I IFN use is limited by clinical and chemical toxicities, and the induction of antibodies that abrogate their activity in vivo correlated with the loss of clinical benefit. Therefore, we determined whether ingested IFN-alpha was non-toxic and had biological effects in humans. Ingested hrIFN-alpha showed no toxicity in normal volunteers or patients with RRMS at doses ranging from 300 to 100,000 units. In subjects with RRMS, a significant decrease in Con A-mediated proliferation and serum soluble intercellular adhesion molecule-1 (sICAM-1), a surrogate measure for disease activity in MS, was found after ingesting 10,000 and 30,000 units IFN-alpha The RRMS subjects also showed decreased IL-2 secretion after ingesting 10,000 units IFN-alpha and decreased IFN-gamma, TGF-beta and IL-10 production after ingesting 30,000 units IFN-alpha. The decreased secretion of IFN-gamma and IL-2 by ingested IFN-alpha suggests that oral IFN-alpha may cause a functional inhibition of Th J-like T helper cells in RRMS, a potential site of intervention at the level of effector T cells in MS. Our studies support the oral use of human IFN-alpha as a biological response modifier in humans.

Administration, Oral↗
PubMed1997

IFN-beta 1b treatment of relapsing multiple sclerosis has no effect on CD3-induced inflammatory or counterregulatory anti-inflammatory cytokine secretion ex vivo after nine months.

Multiple sclerosis (MS) is presumed to be a T-cell mediated chronic inflammatory disease of the central nervous system. We have previously reported that IFN-beta 1b (Betaseron) decreases CD3-mediated TNF-alpha secretion but increases another inflammatory cytokine, IL-6 after three months of treatment. We have now examined cytokine secretion of peripheral blood mononuclear (PMNC) cells after stimulation with OKT3 (anti-CD3) monoclonal antibody (mAb) or Con A in subjects with clinically stable relapsing MS before and three, six and nine months after initiating IFN-beta 1b treatment. At nine months Con A-induced TNF-alpha secretion decreased significantly below baseline but IFN-gamma secretion increased above baseline. There were no significant changes in Con A-induced IL-4 over the six month period and no changes in IL-10 and IL-2 over the nine month period. After nine months on treatment the CD3-induced TNF-alpha and IFN-gamma secretion was not significantly different from the original baseline values. Increased CD3-mediated IL-6 secretion in on-treatment compared to pre-treatment samples at three months gradually declined to baseline values by nine months on-treatment. There was no significant changes from baseline compared to nine months on-treatment in CD3-mediated IL-2, IL-4, IL-10. IFN-beta 1b (Betaseron) treatment has no clear persistent effect on CD3-induced inflammatory or counterregulatory anti-inflammatory cytokine secretion.

Adult↗
PubMed1997

Increased in vitro induced CD4+ and CD8+ T cell IFN-gamma and CD4+ T cell IL-10 production in stable relapsing multiple sclerosis.

Multiple sclerosis (MS) is presumed to be a T-cell mediated chronic inflammatory disease of the central nervous system. Investigators previously demonstrated increased IFN-gamma (pro-inflammatory) and IL-10 (counterregulatory anti-inflammatory) in MS. The balance of pro-inflammatory and counterregulatory anti-inflammatory cytokines may be important in the stabilization of disease activity. Purified CD4+ and CD8+ T cells from patients with clinically definite, stable relapsing MS (RRMS) were stimulated by anti-CD3 mAb or Con A for 48 hours and cytokine supernatants analysed for production of IL-2, IL-6, IFN-gamma, TNF-alpha (potential pro-inflammatory) and IL-4, IL-10, and TGF-beta (potential counterregulatory anti-inflammatory). Con A activated CD4+ and CD8+ T cell proinflammatory cytokine IL-2 secretion, CD4+ T cell IL-6 secretion, CD4+ and CD8+ T cell TNF-alpha secretion and CD8+ T cell IFN-gamma secretion was decreased significantly in RRMS subjects compared to controls. CD3 activated CD4+ and CD8+ T cell IL-6 secretion and CD4+ T cell TNF-alpha secretion was significantly decreased in MS subjects compared to controls. In contrast, there was increased CD3-induced IFN-gamma in both CD4+ and CD8+ T cells and counterregulatory anti-inflammatory CD3-induced IL-10 secretion in CD4+ T cells in RRMS compared to controls. These data suggest that an equilibrium of a pro-inflammatory (IFN-gamma) and a counterregulatory anti-inflammatory (IL-10) cytokine may define stable clinically definite early RRMS.

CD3 Complex↗
PubMed1996

Multiple sclerosis: clinical presentation, diagnosis and treatment.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system and is associated with periods of disability (relapse) alternating with periods of recovery (remission) and often results in progressive neurologic disability. Scientists believe that multiple sclerosis may be a T cell-mediated autoimmune disease. Treatment with high-dose pulses of intravenous methyl-prednisolone is usually associated with a good outcome in the short term. A recent study suggests that interferon beta-1b may decrease the number of relapses in relapsing-remitting multiple sclerosis by 30 percent and also may decrease the development of new central nervous system lesions. Recently, another clinical trial of interferon beta-1a showed a 31 percent reduction in relapse rate and a significant reduction in the average number of active lesions. A third trial showed that 20 mg of copolymer-1, a random polymer of glutamic acid, lysine, alanine and tyrosine, reduced relapses by 21 percent without significant side effects. Further investigation is needed, but these new treatments show great promise in alleviating this difficult clinical problem.

Adrenal Cortex Hormones↗
PubMed1996

Oral administration of IFN-alpha is superior to subcutaneous administration of IFN-alpha in the suppression of chronic relapsing experimental autoimmune encephalomyelitis.

We have previously demonstrated that type I IFNs administered orally (p.o.) suppress clinical relapse in murine chronic relapsing experimental autoimmune encephalomyelitis (CR-EAE), inhibit clinical attacks at doses equivalent to ineffective parenteral (s.c.) doses in acute rat EAE, and decrease the adoptive transfer of EAE. We therefore examined the optimal clinical p.o. dose of murine species-specific IFN-alpha for suppression of relapse attacks and compared it to s.c. administered IFN-alpha in a dose-response experiment in the chronic EAE model. The optimal clinically effective dose for suppression of EAE of p.o. administered murine species-specific IFN-alpha was 10 units and for s.c. administered was 100 units, although the optimal p.o. dose was much more clinically effective than the optimal s.c. dose. Con A- and MT-induced spleen cell proliferation was inhibited by p.o. IFN-alpha, as was Con A-induced IL-2 secretion, but s.c. IFN-alpha did not inhibit the Con A-induced proliferation in spleen cells. Oral IFN-alpha inhibited the mitogen-induced production of IL-2 and IFN-gamma, but s.c. IFN-alpha increased MT-induced IFN-gamma and IL-6 secretion in spleen cells and Con A-induced IL-6 and MT-induced IL-2 and IL-6 in lymph node cells. The oral route is a convenient drug delivery system that may allow the use of lower doses of cytokines and provide enhanced efficacy via unique and potent immunoregulatory circuits without generating additional inflammatory cytokines that may counteract the beneficial effects of s.c. administered type I IFNs.

Administration, Oral↗
PubMed1996

Interferon-beta 1b treatment decreases tumor necrosis factor-alpha and increases interleukin-6 production in multiple sclerosis.

MS is presumed to be a T-cell-mediated chronic inflammatory disease of the CNS. We examined proliferation and cytokine secretion of mononuclear cells after stimulation with OKT3 [anti-CD3] monoclonal antibody (MAb) or concanavalin A (Con A) in subjects with stable relapsing-remitting MS (RR MS) before and after initiating interferon (IFN)-beta 1b treatment. There was no significant difference in pretreatment to on-treatment anti-CD3 mAb or Con A-induced proliferation in RR MS patients. There was significantly increased Con A-induced secretion of tumor necrosis factor (TNF)-alpha, IFN-gamma, interleukin (IL)-2, IL-6, and IL-10 and decreased IL-4 secretion in on-treatment compared with pretreatment peripheral blood mononuclear cell samples. However, on-treatment CD3-mediated secretion of TNF-alpha was significantly decreased, and IL-6 secretion was significantly increased compared with pretreatment values. IFN-gamma was also decreased in on-treatment cultures stimulated with anti-CD3 MAb, but these values did not reach statistical significance. Systemic side effects from IFN-beta 1b were associated with increased IL-6 secretion. There were no significant changes in CD3-mediated IL-4, IL-10, transforming growth factor (TGF)-beta, or IL-2 secretion or Con A-induced TGF-beta secretion. IFN-beta 1b (Betaseron) decreases CD3-mediated TNF-alpha secretion but increases another inflammatory cytokine, IL-6, that could potentially counteract its beneficial immunomodulatory effects.

Autoimmune Diseases↗
PubMed1996

Oral administration of type I interferon modulates the course of experimental allergic neuritis.

We investigated the effect of oral administration of type I interferon (IFN) in experimental allergic neuritis (EAN) in Lewis rats immunized with bovine peripheral nerve myelin. Starting at 7 days preceding immunization, rats were fed daily until sacrifice either with 5000 U rat IFN-alpha/beta or mock-IFN. The clinical severity of EAN was significantly reduced in IFN-alpha/beta fed animals compared to mock-IFN fed controls. Demyelination, but not inflammation, was decreased in IFN-alpha/beta fed compared to mock-IFN fed rats at day 20 after immunization. In situ IFN-gamma production and inflammation were reduced when evaluated by immunocytochemistry at day 13 after immunization. Spleen cells from IFN-alpha/beta fed compared to mock-IFN fed EAN rats showed significantly reduced proliferation to stimulation with Con A or peripheral nerve myelin. IFN-gamma production in draining lymph node cells was significantly reduced after stimulation with bovine peripheral nerve myelin. Our data suggest that oral administration of IFN-alpha/beta reduces the severity of EAN, possibly by a reduction in IFN-gamma production.

Administration, Oral↗
PubMed1995

Decreased CD3-mediated interferon-gamma production in relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that has been postulated to be T-cell mediated. We examined the proliferation and cytokine secretion of mononuclear cells after stimulation with OKT3 (anti-CD3) monoclonal antibody concanavalin A, or ionomycin plus myristic acid palmityl ester in subjects with stable relapsing-remitting MS. Control subjects demonstrated good proliferation to anti-CD3 monoclonal antibody whereas subjects with relapsing-remitting MS showed a significantly decreased anti-CD3 monoclonal antibody-mediated response. There was no difference in concanavalin or ionomycin plus myristic acid palmityl ester stimulation between control subjects and MS subjects. Secretion of interferon-gamma was significantly decreased and transforming growth factor-beta was significantly increased from cultures stimulated with anti-CD3 monoclonal antibody, but not ionomycin plus myristic acid palmityl ester or concanavalin A, in MS patients compared to control subjects. Secretion of interleukin-10 and tumor necrosis factor-alpha was not different between control subjects and MS patients following stimulation with anti-CD3 monoclonal antibody, concanavalin A, or ionomycin plus myristic acid palmityl ester, or of interleukin-2 and interleukin-4 following stimulation with anti-CD3 monoclonal antibody or concanavalin A. An abnormality of signal transduction and secretion of the immunomodulatory molecule interferon-gamma may exist in MS via the CD3 T-cell receptor complex.

CD3 Complex↗
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↗