1486 surgery has been associated with high rates (60-70%) of positive blood cultures that frequently include anaerobic streptococci.6 However, we have not found other reports of hepatic abscesses caused by S milleri in patients who have had a splenectomy. Although this pathogen causes hepatic abscesses, even in patients with an intact spleenreports of minor infections in patients without a spleen are urgently needed. Should patients who have a splenectomy receive a short course of antimicrobial prophylaxis before undergoing a procedure, such as dental extraction, which may lead to transient bacteraemia. J. M. LLIBRE Department of Internal Medicine, J. CUCURULL Hospital Sant Jaume, 08370 Calella,
A. ALOY J. A. HERNANDEZ
Barcelona, Spain
1. Shaw JHF, Print CG. Postsplenectomy sepsis. Br J Surg 1989; 76: 1074-81. 2. Hibberd PL, Rubin RH. Approach to immunization of the immunosuppressed host. Infect Dis Clin North Am 1990; 4: 123-42. 3. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 1986; 314: 1593-99. 4. Gopal V, Bisno AL. Fulminant pneumococcal infection in "normal" asplenic hosts. Arch Intern Med 1977; 137: 1526-30. 5. Schwartz B, Facklam RR, Breiman RF. Changing epidemiology of group A streptococcal infection in the USA. Lancet 1990; 336: 1167-71. 6. Lucas Tomas M. Odontogenic septicaemia. Inf Ter Sist Nac Salud 1990; 14: 293-97. 7. Chua D, Reinhart HH, Sobel JD. Liver abscess caused by Streptococcus milleri. Rev Infect Dis 1989; 11: 197-202.
Activity of lansoprazole against Helicobacter pylori
counted by plating dilutions of suspension in triplicate on agar and enumeratory colonies after 5 days. A bactericidal effect (99 9%) was observed after 24 h with long/1 lansoprazole (figure). With as little as 1 mg/l, there was a decrease in viable bacteria. In other experiments, 100 mg/1 produced a 4 log reduction in viable count. Transmission electronmicroscopy of thin sections6 revealed a significant change in the morphology of H pylori. Coccoidal forms, known to be degenerating organisms, appeared after 6 h of contact and affected most bacteria present after 24 h. The main feature was vesicle formation due to a separation between the inner and outer membranes of the bacterial cell wall. This action was not observed after 1 h. We do not know how lansoprazole exerts its action on H pylori but its selectivity for this bacterium is striking. The clinical relevance has yet to be determined. Benzimidazoles have a specific localisation in the gastric mucosa7 but we do not know what the concentration of these protein pump inhibitors is in the mucus layer where H pylori is found. If this concentration proves to be in sufficient to eradicate H pylori-and eradication is the goal if ulcer relapse is to be avoided8-it could be responsible for the clearance observed in some studies and for improved eradication rates when associated with an antimicrobial therapy such as amoxycillin or amoxycillin plus metronidazole. were
Hôpital des Enfants, 33000 Bordeaux, France, and Hôpital St André, Bordeaux
1.
SIR,-Proton pump inhibitors have emerged as potent drugs in the treatment of peptic ulcers and oesophagitis. However, their action against Helicobacter pylori remains controversial. Mainguet et all and Biasco et alz have reported clearance of H pylori after omeprazole alone. Omeprazole in combination therapy led to eradication of H pylori at a higher rate than did amoxycillin alone.3 It is not clear if omeprazole acts only by increasing the pH (thereby improving the action of the antimicrobial agents’) or if it itself has an antimicrobial action, or both. We have done susceptibility tests in vitro using omeprazole (Astra) and lansoprazole (Houde), a novel proton pump inhibitor. Minimum inhibitory concentrations (MIC) of 40 H pylori strains
by a standard agar dilution technique with control drug and Campylobacter jejuni and Escherichia coli as control microorganisms. A bacteriostatic effect was found against H pylori for omeprazole and for lansoprazole but not against Cjejuni or E coli. The MI Cso was lower for lansoprazole than for omeprazole (16 versus 64 mgl). Subsequently, H pylori strain CIP 101260 was used to determine the killing curve of lansoprazole in an in-vitro model with epithelial cells (HEp2) in 25 cm2 tissue culture flasks.S The medium was MEM containing 10% fetal calf serum and 0, 1, 5, and 10 mg/1 of lansoprazole at neutral pH, with incubation at 37°C in a microaerobic atmosphere. At times 0, 1, 6, and 24 h, viable bacteria
were
evaluated
amoxycillin
as
CFU/ftask
Killing
curves
of
lansoprazole against Hpylori-
FRANCIS MEGRAUD LUDMILA BOYANOVA HERVE LAMOULIATTE
Mainguet P, Delmée M, Debongnie JC. Omeprazole, Campylobacter pylori,
and duodenal ulcer. Lancet 1989; ii: 389-90. 2. Biasco G, Miglioli M, Barbara L, et al. Omeprazole, Helicobacter pylori, gastntis, and duodenal ulcer. Lancet 1989; ii: 1403. 3. Unge P, Gad A, Gnarpe H, Olsson J. Does omeprazole improve antimicrobial therapy directed towards gastric Campylobacter pylori in patients with antral gastritis. Scand J Gastroenterol 1989; 24 (suppl 167) 49-54. 4. McNulty CAM, Dent JC, Ford GA, et al. Inhibitory antimicrobial concentrations against Campylobacter pylon m gastric mucosa. J Antimicrob Chemother 1988; 22: 729-38. 5. Mégraud F, Trimoulet P, Lamouliatte H, Boyanova L. Bacterial effect of amoxycillin on Helicobacter pylori in an in vitro model using epithelial cells. Antimicrob Agents Chemother (in press). 6. Néman-Simha V, Mégraud F. In vitro model to study Campylobacter pylori adherence properties. Infect Immun 1988; 56: 3329-33. 7. Helander HF, Ramsay CH, Regardh CG. Localization of omeprazole and metabolites in the mouse. Scand J Gastroenterol 1985; 20 (suppl 108): 95-104. 8. Rauws EAJ, Tytgat GNJ. Cure of duodenal ulcer associated with eradication of Helicobacter pylori. Lancet 1990; 335: 1233-35.
Campylobacter upsaliensis enteritis associated with canine infections SIR,-Animals may be implicated in the spread of Campylobacter in particular dogs have been cited as a probable cause of
jejuni;
infection.1 C upsaliensis may be an unrecognised and frequent cause of diarrhoea in man.2 However, there are no data on the sources of human infection of these organisms. Sandstedt et aP isolated C upsaliensis in faeces from 63 dogs; the organism was found in dogs with diarrhoea as well as in healthy animals. We report C upsaliensis enteritis possibly associated with canine infection. On March 28, 1991, a previously healthy 53-year-old male physician had a temperature of 38’6°C, lower abdominal cramps, nausea, and diarrhoea. Stools were bloody and C upsaliensis was isolated by the filter method.4 Oral amoxycillin and clavulanic acid was started immediately; after 24 h the patient improved and stools became negative for C upsaliensis. A serological response against the isolated strain was shown by western blotting. The only possible factor contributing to infection was exposure to the patient’s 3-year-old healthy dog, and C upsaliensis was isolated from the dog’s stools. Phenotypic characterisation, antibiotic susceptibility, plasmid analysis, protein profiles,4 and immunotyping,s showed that strains isolated from the patient and the dog might be identical. We also investigated the presence of this organism in 42 dogs with diarrhoea; 13 (31 %) proved positive only for C upsaliensis. Thus C upsaliensis may be a frequent cause of diarrhoea in dogs. Doctors should be aware of the prevalence of C upsaliensis and its possible association with diarrhoea, especially in children,2 and that
1487
dogs may be a source of infection, not only for Cjejuni,l but also for C upsaliensis. The need for careful hygiene practices with domestic dogs should be emphasised. WHO
Collaborating Centre for Enteric Campylobacter, St Pieter’s University Hospital, 1000 Brussels,
HERMAN GOOSSENS LINDA VLAES JEAN-PAUL BUTZLER
Belgium
Gynaecology Unit,
ANDRÉ ADNET
Brussels
POL HANICQ SAM N’JUFOM DANIEL MASSART GUIDO DE SCHRIJVER WALTER BLOMME
Medical Laboratory, St-Agatha-Berchem, Brussels
1. Skirrow M. Campylobacter enteritis in dogs and cats: a review. Vet Res Commun 1981; 5: 13-19. 2. Goossens H, Vlaes L, De Boeck M, et al. Is "Campylobacter upsaliensis" an unrecognised cause of human diarrhoea? Lancet 1990; 335: 584-86. 3. Sandstedt K, Ursing J, Walder M. Thermotolerant campylobacter with no or weak catalase activity isolated from dogs. Curr Microbiol 1983; 8: 209-13. 4. Goossens H, Pot B, Vlaes L, et al. Characterization and description of "Campylobacter upsaliensis" isolated from human feces. J Clin Microbiol 1990; 28: 1039-46 5. Burnie JP, Matthews RC. Immunoblot analysis: a new method for fingerprinting of
hospital pathogens. Immunology 1987; 100: 41-46.
Mycobacterium marinum infection from shucking oysters SIR,-A 66-year-old man who had a swollen left hand with six non-draining nodular lesions along the ulnar palm and who had been treated for several weeks unsuccessfully with dicloxacillin was referred to our clinic. Biopsy of a palmar lesion revealed acid-fast bacilli which proved to be Mycobacterium marinum on culture. There was a rapid response to a combination ofco-trimoxazole and rifampicin. 6-8 weeks before the onset of symptoms the patient had harvested and "shucked" one gallon of oysters from a river inlet while on holiday at Point Comfort, Texas. In retrospect, the patient associated abrasions he had received in the ulnar region of his left palm while oyster-shucking with the subsequent nodular lesions. M marinum infection has been associated with injuries in swimming-pools and fish tanks or from dolphin bites, handling fish, boating accidents, and barnacles.1 We know of no earlier reports associated with oyster-shucking, perhaps because experienced oyster-shuckers would be more likely to wear a protective glove. Non-healing lesions on the palm of an oyster-shucker or in patients with minor trauma associated with an aquatic environment should suggest infection with M marinum. The Chief, Navy Bureau of Medicine and Surgery, Washington, DC, Clinical Investigation Program sponsored this case-report (84-16-1968-263).
Department of Internal Medicine, Infectious Disease Division and Department of Clinical Investigation, Naval Hospital, San Diego, California 92134, USA
H. J. BEECHAM, III E. C. OLDFIELD, III D. E. LEWIS
Department of Dermatology, Naval Hospital,
Millinglon, Tennessee 1. Collins CH, Grange JM, Noble WC, Yates MD. man. J Hyg (Camb) 1985; 94: 135-49.
J. L. BUKER Mycobacterium marinum infections in
unresponsiveness via intrathymic inoculation
Induction of
SIR,-Dr Remuzzi and colleagues (March 30, p 750) show that in intrathymic inoculation with donor glomerular antigens, when combined with cyclosporin and corticosteroid immunosuppression, induces prolonged survival of a subsequent kidney allograft in a donor-specific fashion. They conclude that the intrathymic site of inoculation was central to this unresponsiveness. However, intravenous antigen pre-treatment, when combined with
rats
immunosuppressive agents such as monoclonal antibodies to T-cell surface receptors,’ cyclosporin,z or FK-506can also induce unresponsiveness to donor antigens. Protocols have included
antigen pre-treatment with whole bloodbone-marrow cells/ splenocytes,l and extracted histocompatibility antigens.s Waldmann has proposed that such "peripheral tolerance", when induced by monoclonal antibodies to T-cell receptors, may be the product of T-cell receptor occupancy by antigen combined with the simultaneous inhibition of co-stimulator signals.6 It is conceivable that cyclosporin and FK-506, which inhibit T-cell activation but not antigen recognition, also generate unresponsiveness in this way. Remuzzi et al combined antigen pre-treatment with very high doses of cyclosporin and corticosteroid, and it is therefore tempting to ascribe their fmdings to peripheral rather than central tolerance induction and to postulate that alternative sites for donor antigen inoculation, such as intraperitoneal or intravenous administration, would have achieved a similar result. School of Medicine, Rheumatology and Rehabilitation Research Unit, University of Leeds, Leeds LS2 9NZ, UK
DAVID PROPPER
Qin SX, Cobbold S, Benjamin R, Waldmann H. Induction of classical transplantation tolerance in the adult. J Exp Med 1989; 169: 779-94. 2. Miller CM, Martinelli GP, Racelis D, Schanzer H. Prolongation of rat cardiac allografts by pretransplant administration of blood transfusions and cyclosporin A. Transplantation 1982; 33: 335-37. 3. Propper DJ, Woo J, Thomson AW, Catto GRD, MacLeod AM. FK-506: its influence on anti-class 1 MHC alloantibody responses to blood transfusions. Transplantation 1990; 50: 267-71. 4. Homan WP, Williams KA, Millard PR, Morris PJ. Prolongation of renal allograft survival in the rat by pretreatment with donor antigens and cyclosporin A. Transplantation 1981; 31: 423-27. 5 Yasumura T, Kahan BD. Prolongation of rat kidney allografts by pretransplant administration of donor antigen extract or whole blood transfusion combined with cyclosporine. Transplantation 1983; 36: 603-09. 6. Waldmann H. Manipulation of T-cell responses with monoclonal antibodies. Annu 1.
Rev Immunol 1989; 7: 407-44.
** This letter
has been shown
to
Prof
Remuzzi, whose reply
follows.-ED. L.
SIR,-Dr Propper cites several studies in which peripheral tolerance has been obtained by combining antigen administration and simultaneously inhibiting co-stimulatory signals. One1 (refs as in Propper’s letter) shows that transplantation tolerance can be achieved by combining bone-marrow transplantation and treatment with CD4 and CD8 monoclonal antibodies. This induced permanent acceptance of donor skin graft and in-vitro unresponsiveness to donor cells. Substitution of the marrow by another source of antigen (skin) was ineffective and the second skin graft resulted in prompt rejection of both the first and the test grafts independently of the antilymphocyte agents. These experiments indicate that the combination of donor antigens and monoclonal antibodies to T cell surface receptors does not necessarily induce peripheral tolerance. Miller et al2 showed not tolerance, but prolongation of cardiac engraftment in rats by pre-transplant administration of blood transfusion and cyclosporin. In that experiment cyclosporin was administered for 4 days and graft survival was prolonged up to 20 days at most. Similar prolongation rather than tolerance has been obtained by Yasumura et als who combined cyclosporin with donor antigens. Rat kidney allografts survived 25 days on average. In the study by Propper et aP rats received blood transfusion and FK-506 or cyclosporin for as long as 14 days. This suppressed the development of alloantibodies in the rat. These experiments may in time prove relevant in clinical transplantation but this is not a model of graft tolerance and the issue addressed in these experiments (suppression of antibodies mediating hyperacute allograft rejection) is not the one we are looking at with thymus manipulation. Homan et al4 prolonged renal allograft survival by pretreatment with cyclosporin and spleen lymphocytes. CyA was given for the 14 days before transplantation. This study is important but Homan et al gave cyclosporin for 14 days, during which the animals were exposed to spleen lymphocytes on two occasions. The day after cyclosporin was stopped the transplant was done, and was tolerated. We gave cyclosporin for only 2 days, 10 days before kidney grafting, so that animals had no pharmacological immunosuppression at the moment of transplantation.
A. ALOY J. A. HERNANDEZ
Barcelona, Spain
1. Shaw JHF, Print CG. Postsplenectomy sepsis. Br J Surg 1989; 76: 1074-81. 2. Hibberd PL, Rubin RH. Approach to immunization of the immunosuppressed host. Infect Dis Clin North Am 1990; 4: 123-42. 3. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 1986; 314: 1593-99. 4. Gopal V, Bisno AL. Fulminant pneumococcal infection in "normal" asplenic hosts. Arch Intern Med 1977; 137: 1526-30. 5. Schwartz B, Facklam RR, Breiman RF. Changing epidemiology of group A streptococcal infection in the USA. Lancet 1990; 336: 1167-71. 6. Lucas Tomas M. Odontogenic septicaemia. Inf Ter Sist Nac Salud 1990; 14: 293-97. 7. Chua D, Reinhart HH, Sobel JD. Liver abscess caused by Streptococcus milleri. Rev Infect Dis 1989; 11: 197-202.
Activity of lansoprazole against Helicobacter pylori
counted by plating dilutions of suspension in triplicate on agar and enumeratory colonies after 5 days. A bactericidal effect (99 9%) was observed after 24 h with long/1 lansoprazole (figure). With as little as 1 mg/l, there was a decrease in viable bacteria. In other experiments, 100 mg/1 produced a 4 log reduction in viable count. Transmission electronmicroscopy of thin sections6 revealed a significant change in the morphology of H pylori. Coccoidal forms, known to be degenerating organisms, appeared after 6 h of contact and affected most bacteria present after 24 h. The main feature was vesicle formation due to a separation between the inner and outer membranes of the bacterial cell wall. This action was not observed after 1 h. We do not know how lansoprazole exerts its action on H pylori but its selectivity for this bacterium is striking. The clinical relevance has yet to be determined. Benzimidazoles have a specific localisation in the gastric mucosa7 but we do not know what the concentration of these protein pump inhibitors is in the mucus layer where H pylori is found. If this concentration proves to be in sufficient to eradicate H pylori-and eradication is the goal if ulcer relapse is to be avoided8-it could be responsible for the clearance observed in some studies and for improved eradication rates when associated with an antimicrobial therapy such as amoxycillin or amoxycillin plus metronidazole. were
Hôpital des Enfants, 33000 Bordeaux, France, and Hôpital St André, Bordeaux
1.
SIR,-Proton pump inhibitors have emerged as potent drugs in the treatment of peptic ulcers and oesophagitis. However, their action against Helicobacter pylori remains controversial. Mainguet et all and Biasco et alz have reported clearance of H pylori after omeprazole alone. Omeprazole in combination therapy led to eradication of H pylori at a higher rate than did amoxycillin alone.3 It is not clear if omeprazole acts only by increasing the pH (thereby improving the action of the antimicrobial agents’) or if it itself has an antimicrobial action, or both. We have done susceptibility tests in vitro using omeprazole (Astra) and lansoprazole (Houde), a novel proton pump inhibitor. Minimum inhibitory concentrations (MIC) of 40 H pylori strains
by a standard agar dilution technique with control drug and Campylobacter jejuni and Escherichia coli as control microorganisms. A bacteriostatic effect was found against H pylori for omeprazole and for lansoprazole but not against Cjejuni or E coli. The MI Cso was lower for lansoprazole than for omeprazole (16 versus 64 mgl). Subsequently, H pylori strain CIP 101260 was used to determine the killing curve of lansoprazole in an in-vitro model with epithelial cells (HEp2) in 25 cm2 tissue culture flasks.S The medium was MEM containing 10% fetal calf serum and 0, 1, 5, and 10 mg/1 of lansoprazole at neutral pH, with incubation at 37°C in a microaerobic atmosphere. At times 0, 1, 6, and 24 h, viable bacteria
were
evaluated
amoxycillin
as
CFU/ftask
Killing
curves
of
lansoprazole against Hpylori-
FRANCIS MEGRAUD LUDMILA BOYANOVA HERVE LAMOULIATTE
Mainguet P, Delmée M, Debongnie JC. Omeprazole, Campylobacter pylori,
and duodenal ulcer. Lancet 1989; ii: 389-90. 2. Biasco G, Miglioli M, Barbara L, et al. Omeprazole, Helicobacter pylori, gastntis, and duodenal ulcer. Lancet 1989; ii: 1403. 3. Unge P, Gad A, Gnarpe H, Olsson J. Does omeprazole improve antimicrobial therapy directed towards gastric Campylobacter pylori in patients with antral gastritis. Scand J Gastroenterol 1989; 24 (suppl 167) 49-54. 4. McNulty CAM, Dent JC, Ford GA, et al. Inhibitory antimicrobial concentrations against Campylobacter pylon m gastric mucosa. J Antimicrob Chemother 1988; 22: 729-38. 5. Mégraud F, Trimoulet P, Lamouliatte H, Boyanova L. Bacterial effect of amoxycillin on Helicobacter pylori in an in vitro model using epithelial cells. Antimicrob Agents Chemother (in press). 6. Néman-Simha V, Mégraud F. In vitro model to study Campylobacter pylori adherence properties. Infect Immun 1988; 56: 3329-33. 7. Helander HF, Ramsay CH, Regardh CG. Localization of omeprazole and metabolites in the mouse. Scand J Gastroenterol 1985; 20 (suppl 108): 95-104. 8. Rauws EAJ, Tytgat GNJ. Cure of duodenal ulcer associated with eradication of Helicobacter pylori. Lancet 1990; 335: 1233-35.
Campylobacter upsaliensis enteritis associated with canine infections SIR,-Animals may be implicated in the spread of Campylobacter in particular dogs have been cited as a probable cause of
jejuni;
infection.1 C upsaliensis may be an unrecognised and frequent cause of diarrhoea in man.2 However, there are no data on the sources of human infection of these organisms. Sandstedt et aP isolated C upsaliensis in faeces from 63 dogs; the organism was found in dogs with diarrhoea as well as in healthy animals. We report C upsaliensis enteritis possibly associated with canine infection. On March 28, 1991, a previously healthy 53-year-old male physician had a temperature of 38’6°C, lower abdominal cramps, nausea, and diarrhoea. Stools were bloody and C upsaliensis was isolated by the filter method.4 Oral amoxycillin and clavulanic acid was started immediately; after 24 h the patient improved and stools became negative for C upsaliensis. A serological response against the isolated strain was shown by western blotting. The only possible factor contributing to infection was exposure to the patient’s 3-year-old healthy dog, and C upsaliensis was isolated from the dog’s stools. Phenotypic characterisation, antibiotic susceptibility, plasmid analysis, protein profiles,4 and immunotyping,s showed that strains isolated from the patient and the dog might be identical. We also investigated the presence of this organism in 42 dogs with diarrhoea; 13 (31 %) proved positive only for C upsaliensis. Thus C upsaliensis may be a frequent cause of diarrhoea in dogs. Doctors should be aware of the prevalence of C upsaliensis and its possible association with diarrhoea, especially in children,2 and that
1487
dogs may be a source of infection, not only for Cjejuni,l but also for C upsaliensis. The need for careful hygiene practices with domestic dogs should be emphasised. WHO
Collaborating Centre for Enteric Campylobacter, St Pieter’s University Hospital, 1000 Brussels,
HERMAN GOOSSENS LINDA VLAES JEAN-PAUL BUTZLER
Belgium
Gynaecology Unit,
ANDRÉ ADNET
Brussels
POL HANICQ SAM N’JUFOM DANIEL MASSART GUIDO DE SCHRIJVER WALTER BLOMME
Medical Laboratory, St-Agatha-Berchem, Brussels
1. Skirrow M. Campylobacter enteritis in dogs and cats: a review. Vet Res Commun 1981; 5: 13-19. 2. Goossens H, Vlaes L, De Boeck M, et al. Is "Campylobacter upsaliensis" an unrecognised cause of human diarrhoea? Lancet 1990; 335: 584-86. 3. Sandstedt K, Ursing J, Walder M. Thermotolerant campylobacter with no or weak catalase activity isolated from dogs. Curr Microbiol 1983; 8: 209-13. 4. Goossens H, Pot B, Vlaes L, et al. Characterization and description of "Campylobacter upsaliensis" isolated from human feces. J Clin Microbiol 1990; 28: 1039-46 5. Burnie JP, Matthews RC. Immunoblot analysis: a new method for fingerprinting of
hospital pathogens. Immunology 1987; 100: 41-46.
Mycobacterium marinum infection from shucking oysters SIR,-A 66-year-old man who had a swollen left hand with six non-draining nodular lesions along the ulnar palm and who had been treated for several weeks unsuccessfully with dicloxacillin was referred to our clinic. Biopsy of a palmar lesion revealed acid-fast bacilli which proved to be Mycobacterium marinum on culture. There was a rapid response to a combination ofco-trimoxazole and rifampicin. 6-8 weeks before the onset of symptoms the patient had harvested and "shucked" one gallon of oysters from a river inlet while on holiday at Point Comfort, Texas. In retrospect, the patient associated abrasions he had received in the ulnar region of his left palm while oyster-shucking with the subsequent nodular lesions. M marinum infection has been associated with injuries in swimming-pools and fish tanks or from dolphin bites, handling fish, boating accidents, and barnacles.1 We know of no earlier reports associated with oyster-shucking, perhaps because experienced oyster-shuckers would be more likely to wear a protective glove. Non-healing lesions on the palm of an oyster-shucker or in patients with minor trauma associated with an aquatic environment should suggest infection with M marinum. The Chief, Navy Bureau of Medicine and Surgery, Washington, DC, Clinical Investigation Program sponsored this case-report (84-16-1968-263).
Department of Internal Medicine, Infectious Disease Division and Department of Clinical Investigation, Naval Hospital, San Diego, California 92134, USA
H. J. BEECHAM, III E. C. OLDFIELD, III D. E. LEWIS
Department of Dermatology, Naval Hospital,
Millinglon, Tennessee 1. Collins CH, Grange JM, Noble WC, Yates MD. man. J Hyg (Camb) 1985; 94: 135-49.
J. L. BUKER Mycobacterium marinum infections in
unresponsiveness via intrathymic inoculation
Induction of
SIR,-Dr Remuzzi and colleagues (March 30, p 750) show that in intrathymic inoculation with donor glomerular antigens, when combined with cyclosporin and corticosteroid immunosuppression, induces prolonged survival of a subsequent kidney allograft in a donor-specific fashion. They conclude that the intrathymic site of inoculation was central to this unresponsiveness. However, intravenous antigen pre-treatment, when combined with
rats
immunosuppressive agents such as monoclonal antibodies to T-cell surface receptors,’ cyclosporin,z or FK-506can also induce unresponsiveness to donor antigens. Protocols have included
antigen pre-treatment with whole bloodbone-marrow cells/ splenocytes,l and extracted histocompatibility antigens.s Waldmann has proposed that such "peripheral tolerance", when induced by monoclonal antibodies to T-cell receptors, may be the product of T-cell receptor occupancy by antigen combined with the simultaneous inhibition of co-stimulator signals.6 It is conceivable that cyclosporin and FK-506, which inhibit T-cell activation but not antigen recognition, also generate unresponsiveness in this way. Remuzzi et al combined antigen pre-treatment with very high doses of cyclosporin and corticosteroid, and it is therefore tempting to ascribe their fmdings to peripheral rather than central tolerance induction and to postulate that alternative sites for donor antigen inoculation, such as intraperitoneal or intravenous administration, would have achieved a similar result. School of Medicine, Rheumatology and Rehabilitation Research Unit, University of Leeds, Leeds LS2 9NZ, UK
DAVID PROPPER
Qin SX, Cobbold S, Benjamin R, Waldmann H. Induction of classical transplantation tolerance in the adult. J Exp Med 1989; 169: 779-94. 2. Miller CM, Martinelli GP, Racelis D, Schanzer H. Prolongation of rat cardiac allografts by pretransplant administration of blood transfusions and cyclosporin A. Transplantation 1982; 33: 335-37. 3. Propper DJ, Woo J, Thomson AW, Catto GRD, MacLeod AM. FK-506: its influence on anti-class 1 MHC alloantibody responses to blood transfusions. Transplantation 1990; 50: 267-71. 4. Homan WP, Williams KA, Millard PR, Morris PJ. Prolongation of renal allograft survival in the rat by pretreatment with donor antigens and cyclosporin A. Transplantation 1981; 31: 423-27. 5 Yasumura T, Kahan BD. Prolongation of rat kidney allografts by pretransplant administration of donor antigen extract or whole blood transfusion combined with cyclosporine. Transplantation 1983; 36: 603-09. 6. Waldmann H. Manipulation of T-cell responses with monoclonal antibodies. Annu 1.
Rev Immunol 1989; 7: 407-44.
** This letter
has been shown
to
Prof
Remuzzi, whose reply
follows.-ED. L.
SIR,-Dr Propper cites several studies in which peripheral tolerance has been obtained by combining antigen administration and simultaneously inhibiting co-stimulatory signals. One1 (refs as in Propper’s letter) shows that transplantation tolerance can be achieved by combining bone-marrow transplantation and treatment with CD4 and CD8 monoclonal antibodies. This induced permanent acceptance of donor skin graft and in-vitro unresponsiveness to donor cells. Substitution of the marrow by another source of antigen (skin) was ineffective and the second skin graft resulted in prompt rejection of both the first and the test grafts independently of the antilymphocyte agents. These experiments indicate that the combination of donor antigens and monoclonal antibodies to T cell surface receptors does not necessarily induce peripheral tolerance. Miller et al2 showed not tolerance, but prolongation of cardiac engraftment in rats by pre-transplant administration of blood transfusion and cyclosporin. In that experiment cyclosporin was administered for 4 days and graft survival was prolonged up to 20 days at most. Similar prolongation rather than tolerance has been obtained by Yasumura et als who combined cyclosporin with donor antigens. Rat kidney allografts survived 25 days on average. In the study by Propper et aP rats received blood transfusion and FK-506 or cyclosporin for as long as 14 days. This suppressed the development of alloantibodies in the rat. These experiments may in time prove relevant in clinical transplantation but this is not a model of graft tolerance and the issue addressed in these experiments (suppression of antibodies mediating hyperacute allograft rejection) is not the one we are looking at with thymus manipulation. Homan et al4 prolonged renal allograft survival by pretreatment with cyclosporin and spleen lymphocytes. CyA was given for the 14 days before transplantation. This study is important but Homan et al gave cyclosporin for 14 days, during which the animals were exposed to spleen lymphocytes on two occasions. The day after cyclosporin was stopped the transplant was done, and was tolerated. We gave cyclosporin for only 2 days, 10 days before kidney grafting, so that animals had no pharmacological immunosuppression at the moment of transplantation.
