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R Emmons

Publications and source records attributed to R Emmons.

18 recordsLinked to original sources
PubMed2003

Stem cell therapy for autoimmune disease: overview of concepts from the Snowbird 2002 tolerance and tissue regeneration meeting.

Hematopoietic stem cell transplantation as a treatment for autoimmune disease began in 1996 and has subsequently spread worldwide. In Europe phase III trials have opened, while in America phase III trials are being designed and funded by the National Institutes of Health. On 6 June 2002, clinicians and scientists from around the world met at Snowbird, Utah to discuss the results and future directions of stem cell therapy for autoimmune diseases. What follows are general concepts from chairpersons of this meeting.

Autoimmune Diseases↗
PubMed2001

Fine tuning of TCR signaling by CD5.

Current data indicate that CD5 functions as an inhibitor of TCR signal transduction. Consistent with this role, thymocyte selection in TCR transgenic/CD5(-/-) mice is altered in a manner suggestive of enhanced TCR signaling. However, the impact of CD5 deletion on thymocyte selection varies depending on the transgenic TCR analyzed, ranging from a slight to a marked shift from positive toward negative selection. An explanation for the variable effect of CD5 on selection is suggested by the observation that CD5 surface expression is regulated by TCR signal intensity during development and CD5 surface levels on mature thymocytes and T cells parallel the avidity of the positively selecting TCR/MHC/ligand interaction. In this study, we generated mice that overexpress CD5 during thymocyte development (CD5-tg), and then examined the effect of CD5 overexpression or CD5 deletion (CD5(-/-)) on selection of thymocytes that express the same TCR transgenes. The results demonstrate that the effect on thymocyte selection of altering CD5 expression depends on the avidity of the selecting interaction and, consequently, the level of basal (endogenous) CD5 surface expression. Substitution of endogenous CD5 with a transgene encoding a truncated form of the protein failed to rescue the CD5(-/-) phenotype, demonstrating that the cytoplasmic domain of CD5 is required for its inhibitory function. Together, these results indicate that inducible regulation of CD5 surface expression during thymocyte selection functions to fine tune the TCR signaling response.

Animals↗
PubMed2001

Stem cell engraftment strategies.

The donor stem cell phenotype and host microenvironment determine the outcome of a stem cell transplant. In a series of transplant studies in syngeneic male to female or congenic Ly5.1/Ly5.2 models in which hosts have received no or minimal irradiation (100 cGy), evidence overwhelmingly supports the concept that syngeneic engraftment is determined by stem cell competition. These approaches can be extended to H-2 mismatched allogeneic mouse combination when antigen pre-exposure and CD40-CD40 ligand antibody blockage are employed. A human trial in patients with resistant neoplasia infusing pheresed blood with 10(8) CD3 cells/kg showed that tumor responses and complete chimerism occur with very low levels of CD34+ cells/kg and that the extent of previous treatment is a critical factor in determining chimerism. A major feature of transplants is the phenotype of the donor stem cell. This phenotype shows dramatic reversible plasticity involving differentiation, adhesion protein expression, and engraftment with cytokine-induced cell-cycle transit. Homing is probably also plastic. Marked fluctuations in engraftment capacity are also seen at different points in marrow circadian rhythm.

Adolescent↗
PubMed1999

Lymphohematopoietic stem cell engraftment.

Traditional dogma has stated that space needs to be opened by cytoxic myeloablative therapy in order for marrow stem cells to engraft. Recent work in murine transplant models, however, indicates that engraftment is determined by the ratio of donor to host stem cells, i.e., stem cell competition. One hundred centigray whole body irradiation is stem cell toxic and nonmyelotoxic, thus allowing for higher donor chimerism in a murine syngeneic transplant setting. This nontoxic stem cell transplantation can be applied to allogeneic transplant with the addition of a tolerizing step; in this case presensitization with donor spleen cells and administration of CD40 ligand antibody to block costimulation. The stem cells that engraft in the nonmyeloablated are in G0, but are rapidly induced (by 12 hours) to enter the S phase after in vivo engraftment. Exposure of murine marrow to cytokines (IL-3, IL-6, IL-11 and steel factor) expands progenitor clones, induces stem cells into cell cycle, and causes a fluctuating engraftment phenotype tied to phase of cell cycle. These data indicate that the concepts of stem cell competition and fluctuation of stem cell phenotype with cell cycle transit should underlie any new stem cell engraftment strategy.

Animals↗
PubMed1999

Safety and cost of hyperhydration for the prevention of hemorrhagic cystitis in bone marrow transplant recipients.

Hemorrhagic cystitis is a major cause of morbidity after bone marrow transplantation. Traditional methods of prevention have included mesna (2-mercaptoethane sodium sulfonate) and bladder irrigation. We report the use of hyperhydration as an alternative to these prophylactic measures. One hundred consecutive patients who underwent autologous or allogeneic bone marrow transplantation received high dose cyclophosphamide with hyperhydration using 5% dextrose normal saline at the rate of 250 ml/h and furosemide to maintain a urine output of >150 ml/h. Seventy-one of these patients also received high dose cyclophosphamide as mobilization chemotherapy. There were no episodes of hemorrhagic cystitis following mobilization chemotherapy. The incidence of hemorrhagic cystitis after transplant conditioning was 7% with 2 patients developing clinically significant hemorrhagic cystitis; one was a severe episode. The cost of hyperhydration was US$ 20 per course as opposed to US$ 1,500 per course for mesna, based on acquisition costs at our institution. We conclude that hyperhydration is a safe, inexpensive means of preventing hemorrhagic cystitis associated with high dose cyclophosphamide in bone marrow transplant recipients.

Adult↗
PubMed1998

Specific requirement for CD3epsilon in T cell development.

T cell antigen receptor (TCR) and pre-TCR complexes are composed of clonotypic heterodimers in association with dimers of signal transducing invariant subunits (CD3gamma, -delta, -epsilon, and zeta). The role of individual invariant subunits in T cell development has been investigated by generating gene-specific mutations in mice. Mutation of CD3gamma, -delta, or zeta results in an incomplete block in development, characterized by reduced numbers of mature T cells that express low levels of TCR. In contrast, mature T cells are absent from CD3epsilon-/- mice, and thymocyte development is arrested at the early CD4(-)CD8(-) stage. Although these results suggest that CD3epsilon is essential for pre-TCR and TCR expression/function, their interpretation is complicated by the fact that expression of the CD3gamma and CD3delta genes also is reduced in CD3epsilon-/- mice. Thus, it is unclear whether the phenotype of CD3epsilon-/- mice reflects the collective effects of CD3gamma, -delta, and -epsilon deficiency. By removing the selectable marker (PGK-NEO) from the targeted CD3epsilon gene via Cre/loxP-mediated recombination, we generated mice that lack CD3epsilon yet retain normal expression of the closely linked CD3gamma and CD3delta genes. These (CD3epsilonDelta/Delta) mice exhibited an early arrest in T cell development, similar to that of CD3epsilon-/- mice. Moreover, the developmental defect could be rescued by expression of a CD3epsilon transgene. These results identify an essential role for CD3epsilon in T cell development not shared by the CD3gamma, CD3delta, or zeta-family proteins and provide further evidence that PGK-NEO can influence the expression of genes in its proximity.

Amino Acid Sequence↗
PubMed1997

Retroviral mediated gene transfer of the Fanconi anemia complementation group C gene to hematopoietic progenitors of group C patients.

Fanconi Anemia (FA) is a rare genetic disorder characterized by progress pancytopenia, congenial abnormalities, and a predisposition to malignancy. Therapy is currently limited to allogeneic marrow transplantation; patients lacking a suitable donor usually die from aplasia or acute leukemia. Recently, mutation in a novel gene named FACC (Fanconi anemia C-complementing) has been identified as causing one type of FA. FACC mutations, which introduce splicing errors or stop codons, have been identified in approximately 15% of FA patients. We have recently been successful in functional complementation of four FA cell lines using retroviral vectors to transfer a copy of the normal FACC gene. We also analyzed the ability of our viral vectors to functionally correct hematopoietic progenitor cells from a patient bearing a splice donor mutation. As for the lymphoid cell lines, these CD34-enriched cells were extremely sensitive to MMC. After infection of these progenitor cells with viral vectors bearing normal FACC, the progenitors gave rise to increased numbers of colonies both in the absence and presence of up to 5nM MMC, whereas control cells were completely destroyed by 1nM MMC. In summary, we have demonstrated that: (1) retroviral vectors can be engineered to transfer a normal FACC gene to FA(C) lymphoid cell lines and primary hematopoietic cells; (2) introduction of a normal FACC gene into CD34+ progenitors markedly enhances their growth in the absence and presence of MMC. This study is designed to determine whether hematopoietic progenitors transduced with the normal FACC gene can be reinfused safely into FA(C) patients. CD34+ cells obtained from G-CSF mobilized peripheral blood will be transduced ex vivo over a 72-hour period in the presence of IL-3, IL-6, and Stem Cell Factor with the FACC retroviral vector. These transduced cells will be reinfused into FA(C) patients. Patients will be monitored for toxicities as well as evidence of successful gene transfer and expression. The procedure will be repeated up to a total of 4 times with each treatment 2-4 months apart. Theoretically, these rescued stem cells should have a selective growth advantage within the hypoplastic FA marrow environment in vivo.

Cell Cycle Proteins↗
PubMed1997

Transduction of hematopoietic stem cells in humans and in nonhuman primates.

Primitive hematopoietic progenitor and stem cells have been pursued as highly desirable targets for genetic therapy. Retroviral vectors have been used for the majority of preclinical and clinical studies directed at these cells; however, both preclinical and early clinical studies indicate that the gene transfer efficiency of the current generation of vectors using known transduction conditions into primate and human repopulating stem cells is too low to be of clinical utility in most situations. In this presentation I will summarize the status of our completed and ongoing clinical genetic marking trials, and describe our efforts in the laboratory and use of primate transplantation models to improve on these results.

Animals↗
PubMed1993

Comparison of bronchodilator effects of fenoterol/ipratropium bromide and salbutamol in patients with chronic obstructive lung disease.

A double-blind, randomized cross-over trial was carried out in 24 patients with chronic airflow obstruction. The patients were required to demonstrate a minimum 15% absolute increase in forced expiratory volume (FEV1) after a standard dose (0.4 mg) of fenoterol (F). On a separate occasion the effect of ipratropium bromide (IB; 0.04 mg) on FEV1 was tested also; according to the increase in FEV1 the patients were grouped into IB responders (delta FEV1 > 15%) and IB nonresponders (delta FEV1 < 15%). Two puffs of F/IB (0.1 mg/0.04 mg), salbutamol (S; 0.2 mg) and placebo (P) were given by metered-dose inhaler at the same time of the day on three different occasions. FEV1 and specific airway resistance (sRaw) were assessed before and at specific intervals following inhalation. The results showed that F/IB and S produced similar maximal increases in FEV1 (delta FEV1 32% for F/IB and 31% for S) and decreases in sRaw (delta sRaw 24% for F/IB and 21% for S). These effects were significantly different both from baseline values and from P. FEV1 was still significantly different 8 h after inhalation from P in the F/IB group, but not in the group that received S. The effect of IB on FEV1 in the pretest was compared with the subsequent response to F/IB. In IB responders F/IB seemed to produce slightly more effective bronchodilation. Side effects were minimal and clinically insignificant. In conclusion, F/IB, with its ability to effect sustained bronchodilation without adverse side effects, is a viable alternative to a monotherapy in chronic obstructive pulmonary disease.

Aerosols↗
PubMed1993

A suburban focus of endemic typhus in Los Angeles County: association with seropositive domestic cats and opossums.

Thirty-three cases of locally acquired murine typhus were reported in Los Angeles County residents from May 1984 through February 1988. Only eight cases were reported over the previous 20-year period. Thirty (91%) cases resided within a suburban area encompassing approximately 50 km2 in northcentral Los Angeles or had contact with an animal from this area. Serologic testing (complement fixation and indirect fluorescent antibody) of selected animals in close association with human cases revealed a high prevalence of seropositivity among domestic cats and opossums. Nine (90%) of 10 resident cats tested had demonstrable antibody titers compared with none (0%) of 20 cats from a control area (P < 0.001). Suburban typhus cases were more likely than neighborhood controls to own a cat or dog (odds ratio = 6.9, 95% confidence interval = 1.8, 25.9, P = 0.002). Sixteen (42%) of 38 opossums trapped in close proximity to the residences of cases were seropositive versus none (0%) of 36 opossums from control areas (P < 0.001) A low frequency (2.8%) of seropositivity was found in commensal rodents, and the classic vector of murine typhus, Xenopsylla cheopis, was not found. Ectoparasite indices form seropositive opossums revealed heavy infestations with the cat flea, Ctenocephalides felis (mean flea count = 104.7), a species that readily bites humans. These data provide evidence that a suburban focus of murine typhus exists in Los Angeles that differs substantially from the classic transmission cycle, and that cats, opossums and C. felis may play an important role in the occurrence of human cases.

Adolescent↗
PubMed1993

Changes in immunological parameters during interleukin 2 and interferon 2 alpha treatment of recurrent renal cell carcinoma and malignant melanoma.

Immunological parameters were studied in patients with either advanced renal cell cancer (n = 7) or advanced malignant melanoma (n = 6) during treatment with a low-dose continuous intravenous treatment with human recombinant interleukin-2 (hr IL-2) and recombinant interferon alpha-2a. Before treatment, natural killer (NK) cell activity was found to be significantly lower in these patients than in 10 normal controls. However, the numbers of NK cells in circulation were equivalent; following incubation of the patients' peripheral blood mononuclear cells (PBMC) with IL-2 for three days normal lymphokine activated killer (LAK) cell activities were induced. Thus, in-vitro incubation with IL-2 appeared to overcome a defect in NK activity. We next examined the effect of IL-2/IFN alpha therapy on in-vitro LAK induction. Treatment significantly increased in-vitro LAK activity in eight of nine patients tested, although in-vivo LAK cell activity was not altered during treatment. The numbers of NK cells (CD16+ CD56+) in peripheral blood showed a significant increase in seven of ten patients as a result of treatment. The three patients who showed the best clinical response also showed the highest increase in expression of these phenotypic markers. T cells were found to be activated in 8/10 patients as indicated by increased co-expression of CD3 with CD25 after completion of 4-day continuous intravenous infusion of IL2. Four days before the start of treatment, cancer patient PBMC stimulated with concanavalin A (con A) produced significantly greater amounts of TNF compared to normal controls. In-vitro inducible TNF was found to decrease following treatment. Since IL-2 production and lymphocyte proliferation in response to Con A were normal in the patient group and were not altered by treatment, the reduction in TNF levels seemed not to be a general inhibitory effect. Further study of these and other changes in the immune system during IL-2/IFN alpha treatment may help to understand how these immunoregulators cause tumour destruction and to predict their usefulness in individual patients.

Adult↗
PubMed1991

Thyroid dysfunction can predict response to immunotherapy with interleukin-2 and interferon-2 alpha.

Thyroid dysfunction is a well-recognised side-effect of treatment with interleukin-2 (IL2). We assessed the correlation between the development of abnormal thyroid function and tumour response in 13 patients receiving IL2 and interferon-2 alpha (IFN2 alpha) for advanced malignancy. Seven patients had normal thyroid function during treatment, and all of these patients have since died of progressive disease. Of six patients who did develop thyroid dysfunction during treatment, one patient has died of progressive disease. However, statistically we were unable to confirm a definite correlation between the development of thyroid dysfunction and survival in this small group of patients.

Adult↗
PubMed1988

Colored silver-intensified gold technique for light microscopy.

The development of silver-intensified immunogold-labeled antibodies for light microscopy described by Fritz et al. (4) has been investigated. Principles and chemistries used in color photographic science have been applied to immunogold enhancement. In this technique, colloidal gold acts as the catalytic center for the reduction of silver ions to metallic silver with subsequent color development in the presence of hydroquinone. Silver ions and hydroquinone are adsorbed onto the surface of colloidal gold. The reduction of silver ions to metallic silver is further catalyzed by autometallography. The colored-SIG technique offers several advantages. It has sensitivity comparable to the silver-intensified gold (SIG) method and greater sensitivity than immunoenzymatic procedures, takes approximately one hour, results in one of three color reaction products (magenta, cyan, or yellow), and produces better contrast between the reaction products and the background (Figure 1). Thus, this method should prove useful in double- and even triple-staining procedures.

Gold↗
PubMedDate not supplied

Topical transforming growth factor-beta3 in the prevention or alleviation of chemotherapy-induced oral mucositis in patients with lymphomas or solid tumors.

Transforming growth factor (TGF)-beta3 has been hypothesized to prevent or alleviate oral mucositis (OM) in cancer patients receiving high-dose chemotherapy (CT). Two double-blind, placebo-controlled, multicenter, phase II studies of TGF-beta3 were initiated in the United States, Europe, and Argentina in patients with lymphomas or solid tumors who were receiving highly stomatotoxic CT regimens. Patients were to apply 10-mL mouthwash applications of TGF-beta3 (25 microg/mL) or placebo four times daily (or twice daily) 1 day before and all days during CT. The patients were subsequently evaluated for OM incidence, severity, and duration using National Institute of Cancer Common Toxicity Criteria (NCI-CTC) criteria and an objective scoring system (1). After the start of the trials, negative results from new preclinical studies suggesting suboptimal formulation and/or dosing led to an interim analysis of the ongoing clinical trials. One hundred fifty-two patients from the combined studies were included in the interim analysis, with 116 patients on the TGF-beta3 four times daily and placebo arms. Most (72%) patients had breast cancer, 22% had lymphomas, and 6% had other solid tumors. Although 98% (149 of 152) of patients experienced adverse events, only 14% (22 of 152) experienced events that were judged as possibly or probably related to the study drug (primarily gastrointestinal symptoms). No clinically relevant differences were seen between the treatment and placebo arms regarding safety, nor was there evidence for systemic absorption of TGF-beta3. Finally, there was no advantage of TGF-beta3 treatment regarding the incidence (TGF-beta3 four times daily versus placebo [46% versus 47%]), onset, or duration of NCI-CTC grade 3 or 4 OM. For this dose, formulation, regimen. and patient population, TGF-beta3 was not effective in the prevention or alleviation of CT-induced OM.

Adult↗
PubMedDate not supplied

Cutaneous dissemination of herpes simplex virus in individuals fifteen years of age and older.

We have reported the case histories of two individuals with underlying atopic dermatitis who developed extensive vesicular eruptions. In both cases herpes simplex virus type l was isolated from skin lesions and both individuals ultimately recovered. These two cases represent only the third and fourth instances of this syndrome proven to be caused by herpes simplex virus type l that have been reported in older individuals. In addition we have reviewed the literature relative to cutaneous disseminated herpes simplex virus infections occurring in individuals over the age of 15 and have presented a comprehensive overview of this disease.

Adolescent↗