Biomedical subjects
C H Kirkpatrick
Publications and source records attributed to C H Kirkpatrick.
Purification of transfer factors.
Transfer factor activities have been studied in both clinical and basic science settings for several decades. Until now, highly purified transfer factors that are suitable for molecular analysis have not been available. This has impeded progress towards understanding the molecular and cellular basis of the activities of these important inducers of cell-mediated immune responses. Murine transfer factors with specificities for chicken egg albumin or horse spleen ferritin were purified to virtual homogeneity using a combination of affinity chromatography and reversed-phase and polytypic high performance liquid chromatography (hplc). Transfer factors prepared by this methodology were recovered in high yield and in biologically-active, antigen-specific forms. The purified materials were further analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis, chromatographic methods and an in vivo assay for immunological activity. For the first time definitions for unit transfer factor activity and specific activity are introduced. The results of these experiments indicate that transfer factors are a family of highly polar, hydrophilic molecules of low molecular weight (approximately 5,000) which are produced in small quantities by lymphoid cells and which have potent biological activity. The availability of purified transfer factors should facilitate definitive studies into the nature and mechanisms of production and action of these molecules.
Interferons 1992. How much of the promise has been realised?
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Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study.
An observational surveillance study was conducted to monitor the safety and effectiveness of treatment with Digoxin Immune Fab (Ovine) (Digibind) in patients with digitalis intoxication. Before April 1986, a relatively limited number of patients received treatment with digoxin-specific Fab fragments through a multicenter clinical trial. Beginning with commercial availability in July 1986, this study sought additional, voluntarily reported clinical data pertaining to treatment through a 3 week follow-up. The study included 717 adults who received Digoxin Immune Fab (Ovine). Most patients were greater than or equal to 70 years old and developed toxicity during maintenance dosing with digoxin. Fifty percent of patients were reported to have a complete response to treatment, 24% a partial response and 12% no response. The response for 14% of patients was not reported or reported as uncertain. Six patients (0.8%, 95% confidence interval 0.3% to 1.8%) had an allergic reaction to digoxin-specific antibody fragments. Three of the six had a history of allergy to antibiotic drugs. Twenty patients (2.8%, 95% confidence interval 1.7% to 4.3%) developed recrudescent toxicity. Risk of recrudescent toxicity increased sixfold when less than 50% of the estimated dose of antibody was administered. A total of 215 patients experienced posttreatment adverse events. The events for 163 patients (76%) were judged to result from manifestations of underlying disease and thus considered unrelated to Fab treatment. Digoxin-specific antibody fragments were generally well tolerated and clinically effective in patients judged by treating physicians to have potentially life-threatening digitalis intoxication.
Indomethacin-sensitive monocyte killing defect in a child with disseminated atypical mycobacterial disease.
A child with disseminated disease due to Mycobacterium avium had progressive disease in spite of 4.5 years of therapy with multiple antimicrobial agents selected on the basis of in vitro sensitivity testing of her organism. A defect in monocyte bactericidal activity was detected which was corrected in vitro by exposure of the patient's monocytes to indomethacin and normal serum. Indomethacin therapy resulted in normalization of monocyte bactericidal activity and striking, albeit temporary, clinical improvement.
Allergic histories and reactions of patients treated with digoxin immune Fab (ovine) antibody. The Digibind Study Advisory Panel.
Seven hundred seventeen adult patients with life-threatening digitalis intoxication were treated with Fab fragments of ovine antidigoxin immunoglobulin G (IgG). Results of the efficacy of treatment and adverse effects were collected with standard report forms. Eighty-two (11%) of the patients were recorded as having histories of allergy (71 patients) and/or asthma (11 patients). Of the "allergic" subjects, 35 described reactions to antibiotics, 19 to other medications, 3 to foods, and 2 to pollens; in 12 subjects the etiologic agent was not specified. Six subjects had adverse reactions that were probably or possibly due to allergy to components of the antibody preparation. Of these 4 (5%; 95% confidence interval (Cl) 1.8% to 12%) occurred in the 82 subjects with histories of allergy or asthma and 3 (9%; 95% Cl 1.8% to 23%) of these occurred in the 35 persons with histories of allergy to an antibiotic. In contrast, only 2 (0.3%; 95% Cl 0.04% to 1.1%) similar reactions occurred in the 635 subjects with no histories of allergy or asthma. All reactions responded to symptomatic treatment. The authors conclude that treatment of digitalis intoxication with ovine antidigoxin IgG-Fab (Digibind) is generally well tolerated and allergic reactions are rare. However, there is a significantly increased risk of reactions in patients with histories of allergy or asthma.
Fungal infections in HIV patients.
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Chronic mucocutaneous candidiasis.
Chronic mucocutaneous candidiasis can be defined as a group of syndromes that have as a common feature infections of the skin, nails and mucous membranes with Candida albicans. A variety of disorders including endocrine dysfunctions, alopecia, vitiligo, malabsorption syndromes, neoplasms and other infections may also occur in patients with chronic mucocutaneous candidiasis, but these vary considerably from patient to patient. In most patients with chronic mucocutaneous candidiasis, there are abnormalities of cell-mediated immunity. These may be limited to antigens of Candida albicans, but in some patients they are more extensive and involve the T-lymphocyte-mediated responses to all antigens. These immunologic defects are the factors that predispose patients to infections with opportunistic organisms such as Candida spp. Fungal infections in patients with chronic mucocutaneous candidiasis usually respond to treatment with conventional antifungal agents, but often relapse shortly after treatment is stopped unless the defects in the cell-mediated immune system have been corrected.
Biological response modifiers. Interferons, interleukins, and transfer factor.
Natural consequences of knowledge of the mechanisms that regulate immune responses are the attempts to modify the immune system in order to increase resistance to infectious diseases and to enhance activity against tumor cells. This review describes the roles of interferons and interleukins in immune responses and reviews the experience with transfer factor in treatment of certain diseases.
Murine transfer factor. III. Specific interactions between transfer factor and antigen.
The interactions between dialyzable transfer factor and antigens have been studied. Incubation of transfer factor-containing dialysates from ferritin-sensitized mice or ferritin-coated plastic surfaces removed the antigen-sensitizing activity; incubations of the same preparations on cytochrome c-coated surfaces did not. Similar results were obtained when cytochrome c-transfer factor was studied. Incubation on cytochrome c-coated surfaces removed the activity, but incubation on ferritin-coated surfaces did not. Specific transfer factor activities could be recovered by elution with 8 M urea or acetonitrile. The finding of interactions between transfer factor and antigens provides evidence for a molecular basis of the specificity of the immunologic effects of transfer factor. This technique may also enable us to obtain amounts of specific material that are adequate for chemical analysis.
Mucocutaneous candidiasis and thymoma.
The clinical, pathologic and immunologic features of 27 patients with chronic mucocutaneous candidiasis and thymic tumors are reviewed. This form of chronic candidiasis is unique in that the infections do not occur until after the third decade and, in contrast to patients in whom candidiasis develops during infancy or childhood, it is not accompanied by failure of endocrine organs. Instead, the patients have the disorders that often accompany thymoma, such as myasthenia gravis, hypogammaglobulinemia, and abnormalities of the bone marrow and circulating blood elements. Evidence of impaired cell-mediated immunity was found in 16 of the 21 patients in whom studies were made. The pathogenesis of the immunodeficiency in these patients is unknown. Immunosuppressive activities in the plasma of four patients were found, but none of the five patients in whom the appropriate studies were made was found to have suppressor cells. The features of this disorder are unique enough that it should be considered a syndrome, and patients in whom candidiasis develops during their adult years should be studied for the presence of thymoma.
Third international symposium on transfer factor.
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Ability of dialysates containing transfer factor to induce lymphocyte activating factor by human mononuclear cells.
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Subpopulations of human T lymphocytes. XI. T cells with receptors for IgM or IgG and locomotion of T and non-T cells in peripheral blood from patients with chronic mucocutaneous candidiasis.
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Transfer of cellular immunity with transfer factor.
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Nature and activities of transfer factor.
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Age-related and thymus-dependent rejection of adenovirus 2-transformed cell tumors in the Syrian hamster.
Adenovirus type 2-transformed hamster cell-induced newborn tumor lines were usually rejected when transplanted s.c. into 21-day-old syngeneic, weanling hamsters. The tumor-inducing capacity of two of these lines (Ad2HTL3 and Ad2HTL6) was tested in intact and neonatally thymectomized hosts. After s.c. injection of suspensions prepared from these lines, none of the weaning hamsters developed tumors while 100% of the newborns and 35.2% of neonatally thymectomized, weanling hamsters developed progressively enlarging neoplasms. The susceptibility of neonatally thymectomized hamsters to tumor challenge was directly related to the degree of immunosuppression observed following thymectomy as indicated by the amplitude of the in vitro response of blood leukocytes to concanavalin A. Pretreatment of thymectomized weanlings with syngeneic adult lymphoid cells (i.p.) resulted in a significant reduction in tumor susceptibility (p = 0.03). These findings suggest that acquisition of resistance to adenovirus type 2-transformed cells during the first 21 days of life may be a thymus-dependent cellular immune process.
Rejection of adenovirus 2-transformed cell tumors and immune responsiveness in Syrian hamsters.
Transplantation of adenovirus type 2-transformed cell-induced newborn tumor lines to different aged hamsters revealed that the cell-mediated host defenses responsible for tumor graft rejection matured early in the second week of life. When light microscopic examinations were performed during the course of tumor development, the primary histopathological difference between progressing tumors removed from newborn or thymectomized weanling hamsters and regressing lesions from normal weanlings was the lack of an early, mononuclear cell infiltrate in neoplasms from newborn and thymectomized hosts. These results suggest that the maturation of cellular immunity determines resistance to tumor transplantation in this system. This conclusion was supported by the in vitro detection of concanavalin A-responsive lymphocytes in spleens from tumor-resistant suckling but not tumor-susceptible neonatal hamsters. Although the incomplete seeding of thymus-dependent lymphocytes to the peripheral lymphoid tissues of newborn hamsters may partially explain the deficient concanavalin A responses of neonatal spleen cells, there appears to be an additional requirement for a radioresistant, adherent accessory cell population. These findings suggest that the development of a cell-mediated immune response is necessary for the rejection of adenovirus type 2-transformed cells and transformed cell-induced tumors and that this response requires the interaction of T-cells and accessory cell populations.