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Bone marrow transplantation for phagocytic cell diseases
IIDNI Volume 7, Number 12, December 1988 Editor
Associate Editors
P a u l D. H o e p r i c h , MD Divisionof Infectiousand ImmunologicDiseases Universityof California Davis MedicalCenter
R o g e r G. F i n c h , FRCP, MRC Path Departmentof MicrobialDiseases NottinghamCity Hospital, U.K.
R u t h M . L a w r e n c e , MD Veterans AdministrationOutpatientClinic Sacramento, California
L a r r y K. P i c k e t i n g , MD Program in InfectiousDiseasesand Clinical Microbiology The Universityof Texas MedicalSchoolat Houston
C h a r l e s W . Stratton, MD Departmentof Pathology Vanderbilt UniversityMedicalCenter Nashville, Tennessee
Bone Marrow Transplantation for Phagocytic Cell Diseases Bone Marrow Transplantation for Phagocytic Cell Diseases Alain Fischer New Insights into Encapsulation of Staphylococcus Aureus: Implications for the Development of Vaccines
Alain Fischer 89
92
Mark Huycke Richard Proctor
CASE REPORT
93
Miguel O'Ryan Alan M, Rauch INDEX TO VOLUME 7
Elsevier 0278-2316/88/$0.00 + 2.20
95
Hospital Necker-Enfants Malades Paris, France
Allogeneic bone marrow transplantation (BMT) has been undertaken to try to cure a variety of life-threatening diseases of the phagocytic cells. Agranulocytosis (Kostmann's type), chronic granulomatous disease, leukocyte adhesion deficiency, and the Chediak-Higashi syndrome have been shown to be curable by the replacement of the abnormal marrow. However, the place of such a therapy in the management of these diseases is limited by several drawbacks. HLA identical siblings are available for only one out of three patients. Such transplants may lead to toxic death in a number of cases because of graft versus host disease and infections. Complicating infections are frequent because of preexisting immunodeficiency in the recipient, and because aggressive conditioning regimens are required. Indeed, patients with phagocytic cell disorders have hyperactive bone marrows that require high
doses of chemoradiotherapy for myelablation in order to prevent rejection of the graft. HLA incompatible bone marrow transplants are hampered by an increased risk of graft versus host disease and failure of the graft. Thus, indications for bone marrow transplantation have to be balanced against the natural history of the disease and other available therapies.
Agranulocytosis Infantile agranulocytosis is characterized by a differentiation blockade of the myeloid lineage at the promyelocyte of myelocyte stages. Although granulocyte colonies can be grown in vitro, there is no effective in vivo treatment. Rappaport and co-workers reported the first case of apparent cure of agranulocytosis by allogeneic bone marrow transplantation; no recurrence was observed after more than 5 years post-transplant. This observation proves that the disease is not caused
0278-2316 IDINDN7(12) 89-96, 1988
90 Infectious Diseases Newsletter 7(12) December 1988 by an environmental defect. As is shown in Table 1, two other patients were reported to have been cured by HLA identical allogeneic BMT. It is unclear at the moment whether HLA identical BMT should be proposed for each patient with infantile agranulocytosis. Although the disease is generally thought to be lethal in childhood, several groups have observed that patients may survive solely through the administration of antimicrobics; infections become less frequent and severe after the first years of life. Because it is possible that the use of cytokines such as GMCSF and GCSF may boost the production of granulocytes, perhaps HLA identical BMT should be restricted to patients recovering from very severe infections.
Chronic Granulomatous Disease (CGD) CGD is characterized by defective killing of phagocytized microorganisms by granulocytes and macrophages. The most frequent type is X-linked, inherited, and is secondary to mutation or deletion of the Xlinked gene coding for the beta subunit of cytochrome B. There is an autosomal recessive type of unknown origin that is supposed to be less severe, an observation that has not been confirmed. The first attempts of BMT in CGD were unsuccessful because the conditioning regimen (CR) consisted only of cyclophosphamide (Cy). More aggressive CR, including total body irradiation (TB 1) or high dose busulfan (14 mg/kg) in addition to Cy, allowed sustained engraftment. Mixed engraftment may be observed and remains stable for years. The presence of 15%-20% donor cells was sufficient to ensure a normal, infection-free life in one case. Prevention of bacterial infections by
Table 1. Bone Marrow Transplantation for Phagocytic Cell Diseases Number of Sustained Alive patients engraftment (cured)
Alive (not cured)
Agranulocytosis HLA id a j
inadequate CR c
1
0
0
0
4 2
4 1
3 1
0 1
3
0
0
1
4
4
2
0
H L A id
5
5
l +
HLA non-id
3
3
3
0
~adequate HLA non-id b
CR
Chronic granulomatous disease inadequate CR H L A id j ~adequate
CR
Leukocyte adhesion deficiency Id
0
Chediak-Higashi syndrome H L A id
6
5
5
0
H L A n o n id
2
0
0
0
4
0
0
1
19
18
11 +
7
4
4
Total inadequate CR H L A id ~adequate
CR
H L A n o n id
1a
0 1
• H L A id: HLA identical. b HLA non id: H L A non identical. Inadequate CR (conditioning regimen) = cyclophosphamide 200 rng/kg alone. a Accidental death 1 year post transplant.
the administration of trimethoprimsulfamethoxazole (TMP-SMX) in CGD appears to be extremely effective. Fungal infections are more difficult to treat and to prevent, although the newer azole agents may be of some value. Retrospective studies have shown that death occurs mainly within the first decade of life and that 50% of patients are alive at the age of 10 years. HLA identical BMT may be proposed for young children with CGD if close medical supervision is not possible because of remote habitation or poor compliance with therapy.
Leukocyte Adhesion Deficiency (LAD) The LAD has been recognized in the last few years as an inherited defective expression of three membrane glycoproteins expressed by leukocytes: LFA-1, CR3 or Mac-l, and
p150.95. These glycoproteins mediate adhesion of phagocytic cells to endothelial cell walls, and are thereby critical to migration to sites of infection. The defect leads to severe, recurrent bacterial and fungal infections that cause death in 70% of the cases before the age of 2 years when the disease is severe and consists of complete deficiency of the adhesion molecules. Less severe LAD is associated with less severe infections, allowing survival to adulthood in most cases, although the majority of the patients die before the age of 30 years. A disease previously described as actin deficiency is now recognized as being the LAD. Eight patients with the severe LAD have been treated with BMT; the procedure was successful in 2 out of 5 patients with HLA-identical BMT. Partial engraftment was also observed, and was stable for years (7 years in the first
NOTE: No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. No suggested test or procedure should be carried out unless, in the reader's judgment, its risk is justified. Because of rapid advances in the medical sciences, we recommend that the independent verification of diagnoses and drag dosages should be made. Discussions, views and recommendations as to medical procedures, choice of drugs and drug dosages are the responsibility of the authors. Infectious Diseases Newsletter (ISSN 0278-2316) is issued monthly in one indexed volume per year by Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, New York 10010. Printed in USA at Hanover, PA 17331. Subscription price per year: institutions, $138.00; individuals, $80.00. For postage outside the U.S., add $35.00. Second-class postage paid at New York, NY, and at additional mailing offices. Postmaster: Send address changes to Infectious Diseases Newsletter, Elsevier Science Publishing Co., lnc., 655 Avenue of the Americas, New York, New York 10010. 63 1988 E l s e v i e r S c i e n c e P u b l i s h i n g C o . , Inc. 0278-2316/88/$0.00
+ 2.20
91 Infectious Diseases Newsletter 7(12) December 1988 case). The presence of 20%-30% donor granulocytes is sufficient to prevent infections. It is remarkable to observe that incompatible marrow transplants have been successful in this setting. It is supposed that the defective LFA-1 expression on lymphocytes precludes graft rejection because LFA-1 is required for the adhesion of cytotoxic lymphocytes to their targets. Such observations have led to the effective use of anti-LFA-1 antibodies in the prevention of graft rejection. LAD appears to be a more severe disease than agranulocytosis and CGD because it profoundly affects adhesion, migration, and activation of both granulocytes and macrophages; in addition, lymphocyte functions are affected. Therefore it is logical to propose BMT to every patient with the severe form of LAD.
Chediak-Higashi Syndrome (CHS) The CHS is an autosomal recessive disorder characterized by partial albinism associated with the presence of large granulations in a variety of cell types. It provokes neutropenia and reduces chemotaxis. The disease is nearly always lethal because of the occurrence of an ill-defined, so-called "accelerated phase" defined as lymphoma-like, and marked by a polyvisceral infiltration with lymphocytes and histiocytes. This acute phase may be transiently controlled by chemotherapy (VP 16) and glucosteroids. Death occurs at a mean age of 7 years; 95% of the patients are dead before the age of 20 years. No effective therapy has been found besides allogeneic BMT, which is apparently effective only if aggressive CR is used [TBI, or a combination of busulfan (16 mg/kg) plus cyclophosphamide]. BMT corrects the blood cell anomalies and restores natural killer cell activity, which is consistently deficient in this disease, but does not modify the partial albinism. HLA identical allogeneic BMT is thus the treatment of choice and has to be offered as early as possible in the dis-
ease. The occurrence of an acute phase obliges chemotherapy to obtain remission so that HLA identical BMT may be carried out.
Conclusions When preceded by aggressive CR, HLA identical BMT has been successful in 12 out of 19 patients with different phagocytic cell disorders. There has been no secondary recurrence in this group of patients, now followed for 1 to 9 years post-BMT. BMT is thus an effective therapy in these four diseases. The probability of success is enhanced by transplantation early in life because the risk of graft versus host disease is reduced in young patients. Although the myeloablation has to be aggressive, total body irradiation, which has been associated with secondary late effects such as delayed growth, can be avoided. Indeed, the use of high dose busulfan (14-16 mg/kg) is well tolerated and is not associated with major late complications. One of the most striking observations made in the patients who have received BMT is the frequency of the occurrence of a mixed chimerism with a perfectly mutual tolerance between both cell populations. The presence of as low as 20% of donor cells is sufficient to ensure normal life. Although the HLA identical BMT has been a major improvement in treatment, especially in the therapy of inherited diseases, the treatment of agranulocytosis and CGD by BMT remains to be investigated. Possible advances in therapy, such as the use of cytokines and, eventually, gene therapy ( the X-linked CGD gene has been cloned), may vastly improve treatment. HLA non-identical BMT is a much more difficult approach, although new methodologies have been developed. As a consequence of observations made in the treatment of LAD, the use of anti-LFA-1 antibody may be explored as a means for prevention of failure of grafts. © 1988 Elsevier Science Publishing Co., Inc. 0278-2316/88/$0.00 + 2.20
Bibliography Andersson DC, Springer TA: Leukocyte adhesion deficiency: an inherited defect in the Mac-l, LFA-I and P150,95 glycoproteins. Ann Rev Med 38:175-194, 1987. Blume RS, Wolf SM: The Chediak-Higashi syndrome: studies in four patients and a review of the literature. Medicine 51:247-280, 1972. Dinauer MC, Orkins SH, Brown R, et al: The glycoprotein-encoded by the Xlinked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex. Nature 327:717-719, 1987. Fischer A, Tmng PH, Descamps-Latscha B, et al: Bone marrow transplantation for inborn error of phagocytic cells associated with defective adherence chemotaxis and oxidative response during opsonized particle phagocytosis. Lancet ii:473-476, 1983. Fischer A, Griscelli C, Blanche S, et al: Prevention of graft failure by an antiHLFA-1 monoclonal antibody in HLAmismatched bone marrow transplantation. Lancet ii: 1058-1061, 1986. Fischer A, Griscelli C, Friedrich W, et al: Bone marrow transplantation for immunodeficiencies and osteopetrosis: an European survey 1968-1985. Lancet ii: 1079-1082, 1986. Frayha HH, Biggar WD: Chronic granulomatous disease of childhood: a changing pattern. J Clin Immunol 3:287-294, 1983. Kamani N, August CS, Douglas SD, et al: Bone marrow transplantation in chronic granulomatous disease. J Pediatr 105:42-45, 1984. Kostmann R: Infantile genetic agranulocytosis. Acta Paediatr Scand 45:105, 1956. O'Reilly ILl, Brochstein J, Dinsmore R, et al: Marrow transplantation for congenital disorders. Semin Hematol 21:188-221, 1984. Parkman R: The application of bone marrow transplantation to the treatment of genetic diseases. Science 232:13731378, 1986. Rappaport JM, Parkman R, Newburger P, et al: Correction of infantile agranulocytosis by allogeneic bone marrow transplantation. Am J Med 68:605-609, 1980. Rappaport JM, Newburger PE, Goldblum RM, et al: Allogeneic bone marrow transplantation for chronic granulomatous disease. J Pediatr 101:952-955, Rappaport JM, Smith BR, Parkman R, et
92 Infectious Diseases Newsletter 7(12)
December 1988 al: Application of bone marrow transplantation in genetic diseases. Clinics in Haematol 12:755-773, 1983. Schettni F, DeMattia D, Manzionna MM, et al: Bone marrow transplantation for chronic granulomatous disease associated with cytochrome B deficiency. Ped Hematol Oncol 4:277-279, 1987. Shan PJ, Hugh-Jones K, Hobbs JR, et al: Busulphan and cyclophosphamide cause
little early toxicity during displacement bone marrow transplantation in fifty children. Bone Marrow Transplant 1:193-200, 1986. The Westminster Hospital's Bone Marrow Transplantation. Bone marrow transplant from an unrelated donor for chronic granulomatous disease. Lancet i:210-213, 1977. Virelizier JL, Lagrue A, Durandy A, et al:
Reversal of natural killer defect in a patient with Chediak-Higashi syndrome after bone marrow transplantation. N Engl J Med 305:1055-1056, 1982. Weening RS, Adriaanz LH, Weemaes CMR, et al: Clinical differences in chronic granulomatous disease in patients with cytochrome b-negative or cytochrome b-positive neutrophils. J Pediatr 107:102-106, 1985.
New Insights into Encapsulation of Staphylococcus Aureus: Implications for the Development of Vaccines Mark Huycke Richard Proctor Departments of Medicine and Medical Microbiology, University of Wisconsin, Madison, Wisconsin
Capsules are an important determinant of virulence for many pathogenic bacteria, including pneumococci, group B streptococci, meningococci, Escherichia coli, Klebsiella spp., Pseudomonas spp., Haemophilus influenzae type b, Bacterioides spp., Salmonella spp., Clostridium perfringens, and Staphylococcus aureus.
These surface structures help mediate adherence to tissues and determine initial interactions with most immune mechanisms. While the means by which encapsulated organisms evade normal host defenses and manifest increased virulence are not fully defined, it is clear for Gram-positive bacteria that capsules interfere with effective opsonization by classical and alternative complement pathways as well as by heat-stable opsonic factors in non-immune serum. Exposed peptidoglycan in unencapsulated Grampositive bacteria rapidly activates complement independent of antibody, resulting in deposition of C3b, the major opsonin in human serum. Capsules enhance virulence by concealing cell wall-adherent C3b, and by specifically inhibiting amplified C3b deposition via the alternative complement pathway. As a result
phagocytosis is decreased. Specific immune anti-capsular antibody leads to improved C3b deposition, more efficient opsonophagocytosis, and, hence, more effective killing of encapsulated bacteria. Several years ago Karakawa and Vann described a new scheme for serological typing of S. aureus according to capsular polysaccharides. They have now identified eleven antigenically distinct serotypes and numbered them 1 through 11. Surpisingly, types 5 and 8 comprised over 70% of clinical isolates from many geographic areas (Fig. 1). Encapsulation was a feature in over 90% of strains of S. aureus causing invasive disease and proved to be a stable marker despite numerous passages in vitro. Although heavily encapsulated or mucoid strains are resistant to bacteriophages, strains with smaller capsules, as those generally found in clinical isolates, were susceptible to bacteriophages. As expected, polyclonal or monoclonal antibody to type 5 and 8 capsular polysaccharides resuited in specific phagocytosis of types 5 and 8 S. aureus in vitro. Immunization of mice with capsular polysaccharide from a mucoid strain © 1988 Elsevier Science Publishing Co., Inc. 0278-2316/88/$0.00 + 2.20
of S. aureus protected mice against invasive infection with the homologous strain. In 1978 the first report appeared describing a hitherto unrecognized property of S. aureus, namely specific and irreversible binding by a large, ubiquitous, mammalian glycoprotein called fibronectin. Fibronectin is widely distributed in soluble form in plasma, cerebrospinal fluid, synovial fluid, amniotic fluid, seminal fluid, saliva, and inflammatory exudates of animals. It is also distributed in an insoluble form in tissue where it is covalently cross-linked into multimeric fibers. Several adhesive functions, e.g., cell-to-cell attachment, cell adherence to basement membranes, and clot stabilization, are served by fibronectin. It is also important in wound healing and cell differentiation. Epidemiologic studies show that the number of fibronectin binding sites expressed by S. aureus is significantly associated with invasive infection. In our laboratory, transposon mutagenesis of one strain of S. aureus decreased fibronectin binding 40-fold and resulted in a significant decrease in adherence to heart valve vegetations in an animal model
Associate Editors
P a u l D. H o e p r i c h , MD Divisionof Infectiousand ImmunologicDiseases Universityof California Davis MedicalCenter
R o g e r G. F i n c h , FRCP, MRC Path Departmentof MicrobialDiseases NottinghamCity Hospital, U.K.
R u t h M . L a w r e n c e , MD Veterans AdministrationOutpatientClinic Sacramento, California
L a r r y K. P i c k e t i n g , MD Program in InfectiousDiseasesand Clinical Microbiology The Universityof Texas MedicalSchoolat Houston
C h a r l e s W . Stratton, MD Departmentof Pathology Vanderbilt UniversityMedicalCenter Nashville, Tennessee
Bone Marrow Transplantation for Phagocytic Cell Diseases Bone Marrow Transplantation for Phagocytic Cell Diseases Alain Fischer New Insights into Encapsulation of Staphylococcus Aureus: Implications for the Development of Vaccines
Alain Fischer 89
92
Mark Huycke Richard Proctor
CASE REPORT
93
Miguel O'Ryan Alan M, Rauch INDEX TO VOLUME 7
Elsevier 0278-2316/88/$0.00 + 2.20
95
Hospital Necker-Enfants Malades Paris, France
Allogeneic bone marrow transplantation (BMT) has been undertaken to try to cure a variety of life-threatening diseases of the phagocytic cells. Agranulocytosis (Kostmann's type), chronic granulomatous disease, leukocyte adhesion deficiency, and the Chediak-Higashi syndrome have been shown to be curable by the replacement of the abnormal marrow. However, the place of such a therapy in the management of these diseases is limited by several drawbacks. HLA identical siblings are available for only one out of three patients. Such transplants may lead to toxic death in a number of cases because of graft versus host disease and infections. Complicating infections are frequent because of preexisting immunodeficiency in the recipient, and because aggressive conditioning regimens are required. Indeed, patients with phagocytic cell disorders have hyperactive bone marrows that require high
doses of chemoradiotherapy for myelablation in order to prevent rejection of the graft. HLA incompatible bone marrow transplants are hampered by an increased risk of graft versus host disease and failure of the graft. Thus, indications for bone marrow transplantation have to be balanced against the natural history of the disease and other available therapies.
Agranulocytosis Infantile agranulocytosis is characterized by a differentiation blockade of the myeloid lineage at the promyelocyte of myelocyte stages. Although granulocyte colonies can be grown in vitro, there is no effective in vivo treatment. Rappaport and co-workers reported the first case of apparent cure of agranulocytosis by allogeneic bone marrow transplantation; no recurrence was observed after more than 5 years post-transplant. This observation proves that the disease is not caused
0278-2316 IDINDN7(12) 89-96, 1988
90 Infectious Diseases Newsletter 7(12) December 1988 by an environmental defect. As is shown in Table 1, two other patients were reported to have been cured by HLA identical allogeneic BMT. It is unclear at the moment whether HLA identical BMT should be proposed for each patient with infantile agranulocytosis. Although the disease is generally thought to be lethal in childhood, several groups have observed that patients may survive solely through the administration of antimicrobics; infections become less frequent and severe after the first years of life. Because it is possible that the use of cytokines such as GMCSF and GCSF may boost the production of granulocytes, perhaps HLA identical BMT should be restricted to patients recovering from very severe infections.
Chronic Granulomatous Disease (CGD) CGD is characterized by defective killing of phagocytized microorganisms by granulocytes and macrophages. The most frequent type is X-linked, inherited, and is secondary to mutation or deletion of the Xlinked gene coding for the beta subunit of cytochrome B. There is an autosomal recessive type of unknown origin that is supposed to be less severe, an observation that has not been confirmed. The first attempts of BMT in CGD were unsuccessful because the conditioning regimen (CR) consisted only of cyclophosphamide (Cy). More aggressive CR, including total body irradiation (TB 1) or high dose busulfan (14 mg/kg) in addition to Cy, allowed sustained engraftment. Mixed engraftment may be observed and remains stable for years. The presence of 15%-20% donor cells was sufficient to ensure a normal, infection-free life in one case. Prevention of bacterial infections by
Table 1. Bone Marrow Transplantation for Phagocytic Cell Diseases Number of Sustained Alive patients engraftment (cured)
Alive (not cured)
Agranulocytosis HLA id a j
inadequate CR c
1
0
0
0
4 2
4 1
3 1
0 1
3
0
0
1
4
4
2
0
H L A id
5
5
l +
HLA non-id
3
3
3
0
~adequate HLA non-id b
CR
Chronic granulomatous disease inadequate CR H L A id j ~adequate
CR
Leukocyte adhesion deficiency Id
0
Chediak-Higashi syndrome H L A id
6
5
5
0
H L A n o n id
2
0
0
0
4
0
0
1
19
18
11 +
7
4
4
Total inadequate CR H L A id ~adequate
CR
H L A n o n id
1a
0 1
• H L A id: HLA identical. b HLA non id: H L A non identical. Inadequate CR (conditioning regimen) = cyclophosphamide 200 rng/kg alone. a Accidental death 1 year post transplant.
the administration of trimethoprimsulfamethoxazole (TMP-SMX) in CGD appears to be extremely effective. Fungal infections are more difficult to treat and to prevent, although the newer azole agents may be of some value. Retrospective studies have shown that death occurs mainly within the first decade of life and that 50% of patients are alive at the age of 10 years. HLA identical BMT may be proposed for young children with CGD if close medical supervision is not possible because of remote habitation or poor compliance with therapy.
Leukocyte Adhesion Deficiency (LAD) The LAD has been recognized in the last few years as an inherited defective expression of three membrane glycoproteins expressed by leukocytes: LFA-1, CR3 or Mac-l, and
p150.95. These glycoproteins mediate adhesion of phagocytic cells to endothelial cell walls, and are thereby critical to migration to sites of infection. The defect leads to severe, recurrent bacterial and fungal infections that cause death in 70% of the cases before the age of 2 years when the disease is severe and consists of complete deficiency of the adhesion molecules. Less severe LAD is associated with less severe infections, allowing survival to adulthood in most cases, although the majority of the patients die before the age of 30 years. A disease previously described as actin deficiency is now recognized as being the LAD. Eight patients with the severe LAD have been treated with BMT; the procedure was successful in 2 out of 5 patients with HLA-identical BMT. Partial engraftment was also observed, and was stable for years (7 years in the first
NOTE: No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. No suggested test or procedure should be carried out unless, in the reader's judgment, its risk is justified. Because of rapid advances in the medical sciences, we recommend that the independent verification of diagnoses and drag dosages should be made. Discussions, views and recommendations as to medical procedures, choice of drugs and drug dosages are the responsibility of the authors. Infectious Diseases Newsletter (ISSN 0278-2316) is issued monthly in one indexed volume per year by Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, New York 10010. Printed in USA at Hanover, PA 17331. Subscription price per year: institutions, $138.00; individuals, $80.00. For postage outside the U.S., add $35.00. Second-class postage paid at New York, NY, and at additional mailing offices. Postmaster: Send address changes to Infectious Diseases Newsletter, Elsevier Science Publishing Co., lnc., 655 Avenue of the Americas, New York, New York 10010. 63 1988 E l s e v i e r S c i e n c e P u b l i s h i n g C o . , Inc. 0278-2316/88/$0.00
+ 2.20
91 Infectious Diseases Newsletter 7(12) December 1988 case). The presence of 20%-30% donor granulocytes is sufficient to prevent infections. It is remarkable to observe that incompatible marrow transplants have been successful in this setting. It is supposed that the defective LFA-1 expression on lymphocytes precludes graft rejection because LFA-1 is required for the adhesion of cytotoxic lymphocytes to their targets. Such observations have led to the effective use of anti-LFA-1 antibodies in the prevention of graft rejection. LAD appears to be a more severe disease than agranulocytosis and CGD because it profoundly affects adhesion, migration, and activation of both granulocytes and macrophages; in addition, lymphocyte functions are affected. Therefore it is logical to propose BMT to every patient with the severe form of LAD.
Chediak-Higashi Syndrome (CHS) The CHS is an autosomal recessive disorder characterized by partial albinism associated with the presence of large granulations in a variety of cell types. It provokes neutropenia and reduces chemotaxis. The disease is nearly always lethal because of the occurrence of an ill-defined, so-called "accelerated phase" defined as lymphoma-like, and marked by a polyvisceral infiltration with lymphocytes and histiocytes. This acute phase may be transiently controlled by chemotherapy (VP 16) and glucosteroids. Death occurs at a mean age of 7 years; 95% of the patients are dead before the age of 20 years. No effective therapy has been found besides allogeneic BMT, which is apparently effective only if aggressive CR is used [TBI, or a combination of busulfan (16 mg/kg) plus cyclophosphamide]. BMT corrects the blood cell anomalies and restores natural killer cell activity, which is consistently deficient in this disease, but does not modify the partial albinism. HLA identical allogeneic BMT is thus the treatment of choice and has to be offered as early as possible in the dis-
ease. The occurrence of an acute phase obliges chemotherapy to obtain remission so that HLA identical BMT may be carried out.
Conclusions When preceded by aggressive CR, HLA identical BMT has been successful in 12 out of 19 patients with different phagocytic cell disorders. There has been no secondary recurrence in this group of patients, now followed for 1 to 9 years post-BMT. BMT is thus an effective therapy in these four diseases. The probability of success is enhanced by transplantation early in life because the risk of graft versus host disease is reduced in young patients. Although the myeloablation has to be aggressive, total body irradiation, which has been associated with secondary late effects such as delayed growth, can be avoided. Indeed, the use of high dose busulfan (14-16 mg/kg) is well tolerated and is not associated with major late complications. One of the most striking observations made in the patients who have received BMT is the frequency of the occurrence of a mixed chimerism with a perfectly mutual tolerance between both cell populations. The presence of as low as 20% of donor cells is sufficient to ensure normal life. Although the HLA identical BMT has been a major improvement in treatment, especially in the therapy of inherited diseases, the treatment of agranulocytosis and CGD by BMT remains to be investigated. Possible advances in therapy, such as the use of cytokines and, eventually, gene therapy ( the X-linked CGD gene has been cloned), may vastly improve treatment. HLA non-identical BMT is a much more difficult approach, although new methodologies have been developed. As a consequence of observations made in the treatment of LAD, the use of anti-LFA-1 antibody may be explored as a means for prevention of failure of grafts. © 1988 Elsevier Science Publishing Co., Inc. 0278-2316/88/$0.00 + 2.20
Bibliography Andersson DC, Springer TA: Leukocyte adhesion deficiency: an inherited defect in the Mac-l, LFA-I and P150,95 glycoproteins. Ann Rev Med 38:175-194, 1987. Blume RS, Wolf SM: The Chediak-Higashi syndrome: studies in four patients and a review of the literature. Medicine 51:247-280, 1972. Dinauer MC, Orkins SH, Brown R, et al: The glycoprotein-encoded by the Xlinked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex. Nature 327:717-719, 1987. Fischer A, Tmng PH, Descamps-Latscha B, et al: Bone marrow transplantation for inborn error of phagocytic cells associated with defective adherence chemotaxis and oxidative response during opsonized particle phagocytosis. Lancet ii:473-476, 1983. Fischer A, Griscelli C, Blanche S, et al: Prevention of graft failure by an antiHLFA-1 monoclonal antibody in HLAmismatched bone marrow transplantation. Lancet ii: 1058-1061, 1986. Fischer A, Griscelli C, Friedrich W, et al: Bone marrow transplantation for immunodeficiencies and osteopetrosis: an European survey 1968-1985. Lancet ii: 1079-1082, 1986. Frayha HH, Biggar WD: Chronic granulomatous disease of childhood: a changing pattern. J Clin Immunol 3:287-294, 1983. Kamani N, August CS, Douglas SD, et al: Bone marrow transplantation in chronic granulomatous disease. J Pediatr 105:42-45, 1984. Kostmann R: Infantile genetic agranulocytosis. Acta Paediatr Scand 45:105, 1956. O'Reilly ILl, Brochstein J, Dinsmore R, et al: Marrow transplantation for congenital disorders. Semin Hematol 21:188-221, 1984. Parkman R: The application of bone marrow transplantation to the treatment of genetic diseases. Science 232:13731378, 1986. Rappaport JM, Parkman R, Newburger P, et al: Correction of infantile agranulocytosis by allogeneic bone marrow transplantation. Am J Med 68:605-609, 1980. Rappaport JM, Newburger PE, Goldblum RM, et al: Allogeneic bone marrow transplantation for chronic granulomatous disease. J Pediatr 101:952-955, Rappaport JM, Smith BR, Parkman R, et
92 Infectious Diseases Newsletter 7(12)
December 1988 al: Application of bone marrow transplantation in genetic diseases. Clinics in Haematol 12:755-773, 1983. Schettni F, DeMattia D, Manzionna MM, et al: Bone marrow transplantation for chronic granulomatous disease associated with cytochrome B deficiency. Ped Hematol Oncol 4:277-279, 1987. Shan PJ, Hugh-Jones K, Hobbs JR, et al: Busulphan and cyclophosphamide cause
little early toxicity during displacement bone marrow transplantation in fifty children. Bone Marrow Transplant 1:193-200, 1986. The Westminster Hospital's Bone Marrow Transplantation. Bone marrow transplant from an unrelated donor for chronic granulomatous disease. Lancet i:210-213, 1977. Virelizier JL, Lagrue A, Durandy A, et al:
Reversal of natural killer defect in a patient with Chediak-Higashi syndrome after bone marrow transplantation. N Engl J Med 305:1055-1056, 1982. Weening RS, Adriaanz LH, Weemaes CMR, et al: Clinical differences in chronic granulomatous disease in patients with cytochrome b-negative or cytochrome b-positive neutrophils. J Pediatr 107:102-106, 1985.
New Insights into Encapsulation of Staphylococcus Aureus: Implications for the Development of Vaccines Mark Huycke Richard Proctor Departments of Medicine and Medical Microbiology, University of Wisconsin, Madison, Wisconsin
Capsules are an important determinant of virulence for many pathogenic bacteria, including pneumococci, group B streptococci, meningococci, Escherichia coli, Klebsiella spp., Pseudomonas spp., Haemophilus influenzae type b, Bacterioides spp., Salmonella spp., Clostridium perfringens, and Staphylococcus aureus.
These surface structures help mediate adherence to tissues and determine initial interactions with most immune mechanisms. While the means by which encapsulated organisms evade normal host defenses and manifest increased virulence are not fully defined, it is clear for Gram-positive bacteria that capsules interfere with effective opsonization by classical and alternative complement pathways as well as by heat-stable opsonic factors in non-immune serum. Exposed peptidoglycan in unencapsulated Grampositive bacteria rapidly activates complement independent of antibody, resulting in deposition of C3b, the major opsonin in human serum. Capsules enhance virulence by concealing cell wall-adherent C3b, and by specifically inhibiting amplified C3b deposition via the alternative complement pathway. As a result
phagocytosis is decreased. Specific immune anti-capsular antibody leads to improved C3b deposition, more efficient opsonophagocytosis, and, hence, more effective killing of encapsulated bacteria. Several years ago Karakawa and Vann described a new scheme for serological typing of S. aureus according to capsular polysaccharides. They have now identified eleven antigenically distinct serotypes and numbered them 1 through 11. Surpisingly, types 5 and 8 comprised over 70% of clinical isolates from many geographic areas (Fig. 1). Encapsulation was a feature in over 90% of strains of S. aureus causing invasive disease and proved to be a stable marker despite numerous passages in vitro. Although heavily encapsulated or mucoid strains are resistant to bacteriophages, strains with smaller capsules, as those generally found in clinical isolates, were susceptible to bacteriophages. As expected, polyclonal or monoclonal antibody to type 5 and 8 capsular polysaccharides resuited in specific phagocytosis of types 5 and 8 S. aureus in vitro. Immunization of mice with capsular polysaccharide from a mucoid strain © 1988 Elsevier Science Publishing Co., Inc. 0278-2316/88/$0.00 + 2.20
of S. aureus protected mice against invasive infection with the homologous strain. In 1978 the first report appeared describing a hitherto unrecognized property of S. aureus, namely specific and irreversible binding by a large, ubiquitous, mammalian glycoprotein called fibronectin. Fibronectin is widely distributed in soluble form in plasma, cerebrospinal fluid, synovial fluid, amniotic fluid, seminal fluid, saliva, and inflammatory exudates of animals. It is also distributed in an insoluble form in tissue where it is covalently cross-linked into multimeric fibers. Several adhesive functions, e.g., cell-to-cell attachment, cell adherence to basement membranes, and clot stabilization, are served by fibronectin. It is also important in wound healing and cell differentiation. Epidemiologic studies show that the number of fibronectin binding sites expressed by S. aureus is significantly associated with invasive infection. In our laboratory, transposon mutagenesis of one strain of S. aureus decreased fibronectin binding 40-fold and resulted in a significant decrease in adherence to heart valve vegetations in an animal model