Basic immunological aspects of botulinum toxin therapy

Abstract

Previous studies in this laboratory had mapped the immune recognition profile of the regions recognized antibodies (Abs) and by T cells on the protective H(C) domain (C-terminal fragment corresponding to residues 855-1296 of the heavy chain) of botulinum neurotoxin serotype A (BoNT/A). The localization of these regions has several potential applications and has provided a basis for the understanding of immunoresistance to treatment. We briefly outline these localized regions and discuss the impact of these findings on the immunotherapeutic applications of BoNT/A. Immunoresistance to toxin therapy can appear in some patients after a few injections with the toxin. Our epitope mapping studies have shown that several factors can influence the immune response to the toxin. These factors include dose, duration of treatment, frequency of immunization, and quality of the toxin. The immune response to the whole toxin is under genetic control, and the response to each epitope is under separate genetic control. Therefore, the appearance of blocking Abs (i.e., immunoresistance) in patients might be controlled by the major histocompatability of the host. Once a patient becomes immunoresistant to one toxin then switching to another toxin will most often be of limited and short-lived benefit, because the patient becomes rapidly immunoresistant to the second toxin. Finally, because of the considerable structural homology between tetanus neurotoxin (TeNT) and BoNTs, it is possible, although not certain, that a prior active immune response to TeNT might play some role in the early appearance on anti-BoNT Abs in some patients.

Recombinant Holotoxoid Vaccine against Botulism

“…Sera from mice immunized with BoNT/A RYM or chemically inactivated BoNT/A toxoid-but not HCR/A-was reactive against LC/A, demonstrating both the antigenicity of LC/A and the specificity of the observed antibody response. The three immunogens stimulated a strong antibody response against HC/A, with similar titers supporting earlier observations that the HCR domain contains immunodominant epitopes (2). Moreover, antibodies to HCR/A, BoNT/A RYM , or BoNT/A toxoid were able to neutralize the activity of the toxin in a cultured neuron model (Fig.…”

Dose‐ and volume dependent‐response to intramuscular injection of botulinum neurotoxin‐A optimizes muscle force decrement in mice

“…32 Identifying the lowest dose capable of producing the desired inhibition in the smallest injection volume is critical for minimizing patient risks associated with BoNTA permeating neighboring muscles and the development of antibody resistance to BoNTA. 8,33 Antibody formation to BoNTA can result from repeated injections administered in a short time period, injections of high number of toxin units from overestimating the U/kg body weight ratio necessary to inhibit response, and the cumulative dose administered over multiple treatments. 33 The use of the uninjected contralateral limb as the control may be considered a limitation; however, this approach was reasonable based on previous results.…”

“…8,33 Antibody formation to BoNTA can result from repeated injections administered in a short time period, injections of high number of toxin units from overestimating the U/kg body weight ratio necessary to inhibit response, and the cumulative dose administered over multiple treatments. 33 The use of the uninjected contralateral limb as the control may be considered a limitation; however, this approach was reasonable based on previous results. Control values generated in the contralateral limb were within the ranges of the previously published injected and uninjected legs MFG data in the same mouse gender and strain.…”

On the enhancement of anti-neurotoxin antibody production by subcomponents HA1 and HA3b of Clostridium botulinum type B 16S toxin-haemagglutinin

“…The therapeutic benefits are of limited duration and toxin injections need to be repeated every 3-6 months. In a very small percentage of patients (less with toxin A than with toxin B) the treatment elicits blocking Ab responses against the correlate toxin, which reduce or completely terminate the patient's responsiveness to further treatment (Göschel et al, 1997;Atassi & Oshima, 1999;Atassi, 2002Atassi, , 2004;…”

“…These include the quality of the antigen and its dose, duration of treatment and frequency of immunization (Atassi, 2002(Atassi, , 2004. It has been well established that the immune responses to a protein are determined to a great extent by its form and by the presence of other proteins in the immunogen (Atassi, 2002(Atassi, , 2004.…”