Phillip J. Baker

Treatment Trials for Post-Lyme Disease Symptoms Revisited

The authors of 4 National Institutes of Health-sponsored antibiotic treatment trials of patients with persistent unexplained symptoms despite previous antibiotic treatment of Lyme disease determined that retreatment provides little if any benefit and carries significant risk. Two groups recently provided an independent reassessment of these trials and concluded that prolonged courses of antibiotics are likely to be helpful. We have carefully considered the points raised by these groups, along with our own critical review of the treatment trials. On the basis of this analysis, the conclusion that there is a meaningful clinical benefit to be gained from retreatment of such patients with parenteral antibiotic therapy cannot be justified.

Common Misconceptions About Lyme Disease

Lyme disease, infection with Borrelia burgdorferi, is a focally endemic tick-transmitted zoonosis. During the 3 decades since the responsible spirochete was identified, a series of misconceptions and misunderstandings have become widely prevalent, leading to frequent misdiagnosis and inappropriate treatment. Persistent misconceptions concern the reliability of available diagnostic tools, the signs and symptoms of nervous system involvement, the appropriate choice and duration of antimicrobial therapy, the curability of the infection, and the cause of symptoms that may persist in some patients after treatment. Concern about disparate perspectives led the Institute of Medicine to review the subject. In this article we review the principal misconceptions, discussing their origins and the best currently available scientific evidence related to each one.

Separation of immunomodulatory effects of mannan from Candida albicans into stimulatory and suppressive components

Mannan extracted from Candida albicans was studied for its immunomodulatory activity on in vivo antibody responses to type III pneumococcal polysaccharide (SSS-III), a helper-T-cell-independent antigen, and to sheep erythrocytes (SRBC), a helper-T-cell-dependent antigen. In some studies, the antibody response to SSS-III was converted to a helper-T-cell-dependent response by attaching it to a carrier (horse erythrocytes, HRBC); this complex then was used to immunize mice primed with a subimmunogenic dose of HRBC. Mannan enhanced the antibody response to both SSS-III and SRBC when administered at the same time or 1 or 2 days after immunogen. However, when both mannan and SSS-III were coated onto HRBC for immunization, either enhancement or suppression was noted; the effect depended upon the amount of mannan used. Larger amounts stimulated, whereas smaller amounts suppressed, the antibody response to SSS-III. The enhancing and suppressive components of mannan could be separated by molecular size or charge by chromatography on Sepharose 4B or on DEAE-Sephadex A-50 columns, indicating that mannan extracts contain individual components having opposing immunomodulatory properties. These components can be separated on the basis of molecular size and charge.

Homeostatic Control of Antibody Responses: A Model Based on the Recognition of Cell-Associated Antibody by Regulatory T Cells

Co-operation between thymus-derived helper cells (helper T cells) and bone marrow-derived precursors of antibody-forming cells (B cells) has not been found to be essential for a normal antibody response to Type n i pneumococcal polysaccharide (SSS-in), a linear polymer composed of identical disaccharide repeating xmits (Humphrey et al. 1964, Davies et al. 1970, Howard et al. 1971, Manning et al. 1972, Baker et al. 1973, How et al. 1964). Consequently, the antibody response to this antigen has been considered to be largely a B cell response in which the antibody produced is predominantly of the yM class (Howard et al. 1971, Baker & Stashak 1969, Barthold et al. 1974a). It has also been shown that the avidity of antibody specific for SSS-DI remains essentially constant over a 10,000-fold range of immunizing doses, and also after reimmunization with high or low doses of antigen, indicating the lack of an antigen-driven cell selection process (Baker et al. 1971b, Siskind & Benacerraf 1969). These findings imply that the antibody response of inbred mice to SSS-III is the result of the direct stimulation by this antigen of a highly restricted population of B cells. Since, for the past few years, the main objective of our work has been to clarify the mechanisms by which antibody synthesis is initiated and controlled following immunization, an antibody response with these character-

IMMUNOLOGICAL PARALYSIS TO TYPE III PNEUMOCOCCAL POLYSACCHARIDE AS ASSESSED BY AN IMMUNO‐PLAQUE PROCEDURE

Two mechanisms have been proposed to explain the development of immunological paralysis or tolerance to pneumococcal polysaccharides. These deal with whether paralysis is the result of the neutralization of antibody by persistent undegraded antigen (the “treadmill” hypothesis) ,l or whether a suppression of antibody synthesis, i.e., a central failure of the immune mechanism, is involved.z These proposed mechanisms are not necessarily mutually exclusive and persuasive evidence has been advanced to support both points of view.l> 3-7 However, in order to evaluate fully the significance of either process in the development of paralysis, more precise quantitative information is required concerning the antibody response to pneumococcal polysaccharides at the cellular level. Recently, we developed an adaptation of the technique of localized hemolysisin-gel that permits one to determine not only the number of antibody-forming cells produced in response to pneumococcal polysaccharides but also the rate at which antibody is synthesized and released by such cells.x,9 By means of this method we have been able to show that while the neutralization of antibody by excess antigen may be a factor in the development of paralysis to large doses of pneumococcal polysaccharides, a central failure of the immune mechanism clearly plays a significant, if not a dominant, role.

Strain differences in the ability of antithymocyte serum (ATS) to enhance the antibody response of inbred mice to type III pneumococcal polysaccharide

Abstract Treatment with antithymocyte serum (ATS), prepared in burros or rabbits, significantly enhanced the antibody response to Type III pneumococcal polysaccharide (SSS-III) in 5 inbred and 2 hybrid strains of mice. The degree of enhancement attained depended upon the dose of ATS employed. Strains of mice differed with respect to the amount of enhancement produced following treatment with a given dose of the same preparation of ATS.

Unorthodox Alternative Therapies Marketed to Treat Lyme Disease

BACKGROUND Some patients with medically unexplained symptoms or alternative medical diagnoses suspect that they chronically suffer from the tick-borne infection Lyme disease. These patients are commonly targeted by providers of alternative therapies. This study was designed to identify and characterize the range of unorthodox alternative therapies advertised to patients with a diagnosis of Lyme disease. METHODS Internet searches using the Google search engine were performed to identify the websites of clinics and services that marketed nonantimicrobial therapies for Lyme disease. We subsequently used the PubMed search engine to identify any scientific studies evaluating such treatments for Lyme disease. Websites were included in our review so long as they advertised a commercial, nonantimicrobial product or service that specifically mentioned utility for Lyme disease. Websites with patient testimonials (such as discussion groups) were excluded unless the testimonial appeared as marketing on a commercial site. RESULTS More than 30 alternative treatments were identified, which fell into several broad categories: these included oxygen and reactive oxygen therapy; energy and radiation-based therapies; nutritional therapy; chelation and heavy metal therapy; and biological and pharmacological therapies ranging from certain medications without recognized therapeutic effects on Borrelia burgdorgeri to stem cell transplantation. Review of the medical literature did not substantiate efficacy or, in most cases, any rationale for the advertised treatments. CONCLUSIONS Providers of alternative therapies commonly target patients who believe they have Lyme disease. The efficacy of these unconventional treatments for Lyme disease is not supported by scientific evidence, and in many cases they are potentially harmful.

The role of antigen in the activation of regulatory T cells by immune B cells

The transfer of B cells from mice immunized with Type III pneumococcal polysaccharide (SSS-III) results in the activation of suppressor and amplifier T cells that control the magnitude of the antibody response in recipient mice, immunized subsequently with SSS-III. Prior treatment of transferred B cells with an excess of enzyme (polysaccharide depolymerase) capable of hydrolyzing SSS-III, does not alter the capacity of these cells to activate regulatory T cells. These findings indicate that the activation of regulatory T cells by immune B cells is not mediated by residual antigen on the surface of transferred cells.

Critical Analysis of Treatment Trials of Rhesus Macaques Infected with Borrelia burgdorferi Reveals Important Flaws in Experimental Design

A critical analysis of two treatment trials of Chinese rhesus macaques infected with Borrelia burgdorferi indicates that insufficient attention was placed on documenting the blood levels, pharmacokinetics, and pharmacodynamic parameters of the antibiotics used in this host. Consequently, it is impossible to conclude that the findings have validity in judging the efficacy of doxycycline or ceftriaxone for the treatment of Borrelia burgdorferi in this animal model.

Lack of involvement of auto-anti-idiotypic antibody in the regulation of oscillations and tolerance in the antibody response to levan

Abstract Bacterial levan (BL) induces a cyclic (oscillatory) antibody response in both euthymic and athymic BALB/c mice. Significant numbers of plaque-forming cells (PFC) making auto-anti-idiotypic antibody directed against a major cross-reactive idiotype expressed on antibodies specific for BL were detected in euthymic—but not athymic—mice. This suggests that auto-anti-idiotypic antibody, the formation of which requires the participation of mature T cells, does not play a decisive role in generating the cyclic patterns observed. However, such antibody might still influence the proportion of PFC making antibody of complementary idiotype. No relationship between the suppressive property of auto-anti-idiotypic antibody and either the induction or maintenance of immunological tolerance to BL was evident.