179
Intestinal secretions were sampled by whole-gut lavage (essentially a gut perfusion, at a rate of 20 ml per min) with ’Golytely’, a commercially available gut cleansing fluid.2 Serum and whole-gut lavage fluid (WGLF) were obtained before and at three weeks after a course of three enteric-coated capsules, each containing 109 live Ty21aorganisms. Isotype-specific antibodies to Ty2la lipopolysaccharide (Sigma) were assayed by ELISA, and expressed in relation to a serum standard arbitrarily designated as containing 1000 units of each class of antibody, IgG, IgA, and IgM. One patient (patient 1) had very high concentrations of serum IgG and IgM antibody before vaccination; in the other subjects concentrations were low. Serum IgA antibody varied from 38-140
units/ml. Serum antibodies did not differ before and after vaccination. Intestinal IgA values (units/ml WGLF) were: MRI, T2 weighted image, showing hyperintense resolution
along right optic
nerve.
The clinical picture in our patient was probably attributable to tetanus toxoid. In experimental allergic neuritis, myelin injury may occur before macrophage-mediated demyelination, and provides support for an early role of serum factorsThe early onset of symptoms in our patient may partly be explained on this basis. We cannot judge how steroids and/or immunoglobulin affected the course and outcome in our patient and others.6 Optic neuritis and myelitis have been reported after rubella vaccination.’ Relapse has been reported with further injections of tetanus toxoid,4 and this should be a consideration in patients such as ours.
Departments of Paediatric Neurology, Neuro-ophthalmology, and Paediatrics, Hacettepe Children’s Hospital, 06100 Ankara, Turkey
HALUK TOPALOGLU MUSTAFA BERKER TULAY KANSU UMIT SAATCI YAVUZ RENDA
1 Immunization Practices Advisory Committee, Centers for Disease Control. Diptheria, tetanus and pertussis guidelines for vaccine prophylaxis and other preventive measures. Ann Intern Med 1981; 95: 723-28. 2. Beghi E, Kurland LT, Mulder DW, Nicolasi A. Brachial plexus neuropathy m the population of Rochester, Minnesota, 1970-1981 Ann Neurol 1985, 18: 320-23. 3 Holliday PL, Baver RB Polyradiculoneuritis secondary to immunization with tetanus and diphtheria toxoids. Arch Neurol 1983; 40: 56-57. 4 Pollard JD, Selby G Relapsing neuropathy due to tetanus toxoid. J Neurol Sci 1978; 37: 113-25. 5 Rosen JL, Brown MJ, Hickey WF, Rostami A. Early myelin lesions m experimental allergic neuritis Muscle Nerve 1990; 13: 629-36. 6. Schlenska GK. Unusual neurologic complications following tetanus toxoid administration. J Neurol 1977, 215: 299-302. 7 Kline LB, Margulies SL, Oh SJ. Optic neuritis and myelitis following rubella vaccination. Arch Neurol 1982; 39: 443-46.
Mucosal
immunity to oral vaccines
SiR,-Your correspondence (Dec 7, p 1455) about the efficacy, formulations, and doses of the oral typhoid vaccine Ty21aa (Oct 26, p 1055) reads strangely to those of us working in clinical gastrointestinal immunology. Large scale field trials have been done to measure protective efficacy without any knowledge of the intestinal antibody status of vaccinees. The only published data showing that the vaccine strain can induce local mucosal immunity seem to be those of Forrest et al,l who investigated healthy Australian volunteers and excluded individuals with a history of salmonella infection or food-poisoning. Most volunteers received doses of the organism one or two log values greater than those used in recent trials. Mucosal immunity is separate from systemic immunity in the types of cells and isotypes of antibody involved, and in the factors that regulate its induction and expression. Surely present methods for testing intestinal secretions should be used to defme the baseline intestinal antibody status of a study population, changes in antibody concentrations after vaccination, and the relation (if any) between serum antibody concentrations, intestinal secretory antibody titres, and clinical protection? We use enteric vaccines as oral immunogens in protocols for investigation of intestinal immunity and its regulatory mechanisms and report our experience with the oral Ty2la vaccine in four healthy individuals.
Pahenf
Prevaccination
Postvaccination*
1 2 3 4
129 9 7-4 6-5 1-8
11 7 12.8 11-7 2-2
*3 weeks after first vaccine dose
Vaccination had no effect in patient 1 with high and patient 4 with very low baseline intestinal IgA antibody. However, there was a striking rise in antibody concentration in patients 2 and 3 with intermediate baseline titres (total intestinal production estimated at 15 360 and 14 040 units/h, respectively). No subject had detectable IgG or IgM intestinal antibody. Thus, the regimen probably boosted intestinal antibody production only in partly primed individuals. These few data, similar experiments with oral killed whole cell/cholera toxin B subunit vaccine,-’ and our findings in volunteers and in patients with coeliac disease, inflammatory bowel disease, and ankylosing spondylitis (refs 4-6, and O’Mahony S, Anderson N, Nuki G, Ferguson A, unpublished) show that gut antibody production can be investigated directly by whole-gut lavage. Our experience also shows that it is misleading to extrapolate determinations of serum or salivary antibodies to the gut.3,4,7 In the complex microenvironment of the gut, and in view of the narrow range of properties of IgA molecules, it should also be recognised that the presence of specific antibody is not necessarily correlated with immunoprotection. Although methods for the measurement of intestinal cellular immunity are not yet fully developed, the humoral component of mucosal immunity can be readily assessed either by duodenal intubation or by use of the gut lavage procedure. Clinical tests of intestinal immunity in the course of oral vaccine development should be more widely used, so that the effects of key variables such as malnutrition or previous antigen exposure are measured rather than assumed. Gastro-Intestinal Unit, Western General Hospital and University of Edinburgh,
Edinburgh EH4 2XU, UK
ANNE FERGUSON JAMAL SALLAM
1. Forrest BD, LaBrooy JT, Beyer L, Dearlove CE, Shearman DJC The human humoral immune response to Salmonella typhi Ty21a. J Infect Dis 1991; 163: 336-45. 2. O’Mahony S, Barton JR, Crichton S, Ferguson A. Appraisal of gut lavage in the study of intestinal humoral immunity. Gut 1990; 31: 1341-44. 3. O’Mahony S. The investigation of human intestinal humoral immunity [MD thesis.] Cork: University of Cork, 1990. 4 O’Mahony S, Arranz E, Barton JR, Ferguson A. Dissociation between systemic and mucosal humoral immune responses in coeliac disease. Gut 1991; 32: 29-35. 5. O’Mahony S, Choudari CP, Barton JR, Walker S, Ferguson A. Gut lavage fluid proteins as markers of activity of inflammatory bowel disease. Scand J Gastroenterol
1991; 26: 940-44. E, O’Mahony S, Barton JR, Ferguson A Immunosenescence and mucosal immunity: significant effects of old age on serum and secretory IgA concentrations and on intraepithelial lymphocyte counts Gut (in press). 7. Barton JR. Human gastrointestinal mucosal secretory immunity: investigation and regulation [PhD thesis.] Edinburgh: University of Edinburgh, 1991. 6. Arranz
Thalassaemia strategy in Sicily S;R,—p-thatassaemia and haemoglobin S carriers make up 5-9% and 2 0%, respectively, of the Sicilian population,"2 and the Sicilian Regional Health Department has taken an active part in tackling this complex medicosocial issue. The department set up fourteen centres, staffed by physicians, nurses, technicians, psychologists, and social workers, to improve the treatment of thalassaemia and
Intestinal secretions were sampled by whole-gut lavage (essentially a gut perfusion, at a rate of 20 ml per min) with ’Golytely’, a commercially available gut cleansing fluid.2 Serum and whole-gut lavage fluid (WGLF) were obtained before and at three weeks after a course of three enteric-coated capsules, each containing 109 live Ty21aorganisms. Isotype-specific antibodies to Ty2la lipopolysaccharide (Sigma) were assayed by ELISA, and expressed in relation to a serum standard arbitrarily designated as containing 1000 units of each class of antibody, IgG, IgA, and IgM. One patient (patient 1) had very high concentrations of serum IgG and IgM antibody before vaccination; in the other subjects concentrations were low. Serum IgA antibody varied from 38-140
units/ml. Serum antibodies did not differ before and after vaccination. Intestinal IgA values (units/ml WGLF) were: MRI, T2 weighted image, showing hyperintense resolution
along right optic
nerve.
The clinical picture in our patient was probably attributable to tetanus toxoid. In experimental allergic neuritis, myelin injury may occur before macrophage-mediated demyelination, and provides support for an early role of serum factorsThe early onset of symptoms in our patient may partly be explained on this basis. We cannot judge how steroids and/or immunoglobulin affected the course and outcome in our patient and others.6 Optic neuritis and myelitis have been reported after rubella vaccination.’ Relapse has been reported with further injections of tetanus toxoid,4 and this should be a consideration in patients such as ours.
Departments of Paediatric Neurology, Neuro-ophthalmology, and Paediatrics, Hacettepe Children’s Hospital, 06100 Ankara, Turkey
HALUK TOPALOGLU MUSTAFA BERKER TULAY KANSU UMIT SAATCI YAVUZ RENDA
1 Immunization Practices Advisory Committee, Centers for Disease Control. Diptheria, tetanus and pertussis guidelines for vaccine prophylaxis and other preventive measures. Ann Intern Med 1981; 95: 723-28. 2. Beghi E, Kurland LT, Mulder DW, Nicolasi A. Brachial plexus neuropathy m the population of Rochester, Minnesota, 1970-1981 Ann Neurol 1985, 18: 320-23. 3 Holliday PL, Baver RB Polyradiculoneuritis secondary to immunization with tetanus and diphtheria toxoids. Arch Neurol 1983; 40: 56-57. 4 Pollard JD, Selby G Relapsing neuropathy due to tetanus toxoid. J Neurol Sci 1978; 37: 113-25. 5 Rosen JL, Brown MJ, Hickey WF, Rostami A. Early myelin lesions m experimental allergic neuritis Muscle Nerve 1990; 13: 629-36. 6. Schlenska GK. Unusual neurologic complications following tetanus toxoid administration. J Neurol 1977, 215: 299-302. 7 Kline LB, Margulies SL, Oh SJ. Optic neuritis and myelitis following rubella vaccination. Arch Neurol 1982; 39: 443-46.
Mucosal
immunity to oral vaccines
SiR,-Your correspondence (Dec 7, p 1455) about the efficacy, formulations, and doses of the oral typhoid vaccine Ty21aa (Oct 26, p 1055) reads strangely to those of us working in clinical gastrointestinal immunology. Large scale field trials have been done to measure protective efficacy without any knowledge of the intestinal antibody status of vaccinees. The only published data showing that the vaccine strain can induce local mucosal immunity seem to be those of Forrest et al,l who investigated healthy Australian volunteers and excluded individuals with a history of salmonella infection or food-poisoning. Most volunteers received doses of the organism one or two log values greater than those used in recent trials. Mucosal immunity is separate from systemic immunity in the types of cells and isotypes of antibody involved, and in the factors that regulate its induction and expression. Surely present methods for testing intestinal secretions should be used to defme the baseline intestinal antibody status of a study population, changes in antibody concentrations after vaccination, and the relation (if any) between serum antibody concentrations, intestinal secretory antibody titres, and clinical protection? We use enteric vaccines as oral immunogens in protocols for investigation of intestinal immunity and its regulatory mechanisms and report our experience with the oral Ty2la vaccine in four healthy individuals.
Pahenf
Prevaccination
Postvaccination*
1 2 3 4
129 9 7-4 6-5 1-8
11 7 12.8 11-7 2-2
*3 weeks after first vaccine dose
Vaccination had no effect in patient 1 with high and patient 4 with very low baseline intestinal IgA antibody. However, there was a striking rise in antibody concentration in patients 2 and 3 with intermediate baseline titres (total intestinal production estimated at 15 360 and 14 040 units/h, respectively). No subject had detectable IgG or IgM intestinal antibody. Thus, the regimen probably boosted intestinal antibody production only in partly primed individuals. These few data, similar experiments with oral killed whole cell/cholera toxin B subunit vaccine,-’ and our findings in volunteers and in patients with coeliac disease, inflammatory bowel disease, and ankylosing spondylitis (refs 4-6, and O’Mahony S, Anderson N, Nuki G, Ferguson A, unpublished) show that gut antibody production can be investigated directly by whole-gut lavage. Our experience also shows that it is misleading to extrapolate determinations of serum or salivary antibodies to the gut.3,4,7 In the complex microenvironment of the gut, and in view of the narrow range of properties of IgA molecules, it should also be recognised that the presence of specific antibody is not necessarily correlated with immunoprotection. Although methods for the measurement of intestinal cellular immunity are not yet fully developed, the humoral component of mucosal immunity can be readily assessed either by duodenal intubation or by use of the gut lavage procedure. Clinical tests of intestinal immunity in the course of oral vaccine development should be more widely used, so that the effects of key variables such as malnutrition or previous antigen exposure are measured rather than assumed. Gastro-Intestinal Unit, Western General Hospital and University of Edinburgh,
Edinburgh EH4 2XU, UK
ANNE FERGUSON JAMAL SALLAM
1. Forrest BD, LaBrooy JT, Beyer L, Dearlove CE, Shearman DJC The human humoral immune response to Salmonella typhi Ty21a. J Infect Dis 1991; 163: 336-45. 2. O’Mahony S, Barton JR, Crichton S, Ferguson A. Appraisal of gut lavage in the study of intestinal humoral immunity. Gut 1990; 31: 1341-44. 3. O’Mahony S. The investigation of human intestinal humoral immunity [MD thesis.] Cork: University of Cork, 1990. 4 O’Mahony S, Arranz E, Barton JR, Ferguson A. Dissociation between systemic and mucosal humoral immune responses in coeliac disease. Gut 1991; 32: 29-35. 5. O’Mahony S, Choudari CP, Barton JR, Walker S, Ferguson A. Gut lavage fluid proteins as markers of activity of inflammatory bowel disease. Scand J Gastroenterol
1991; 26: 940-44. E, O’Mahony S, Barton JR, Ferguson A Immunosenescence and mucosal immunity: significant effects of old age on serum and secretory IgA concentrations and on intraepithelial lymphocyte counts Gut (in press). 7. Barton JR. Human gastrointestinal mucosal secretory immunity: investigation and regulation [PhD thesis.] Edinburgh: University of Edinburgh, 1991. 6. Arranz
Thalassaemia strategy in Sicily S;R,—p-thatassaemia and haemoglobin S carriers make up 5-9% and 2 0%, respectively, of the Sicilian population,"2 and the Sicilian Regional Health Department has taken an active part in tackling this complex medicosocial issue. The department set up fourteen centres, staffed by physicians, nurses, technicians, psychologists, and social workers, to improve the treatment of thalassaemia and
