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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From Research and Development, Australian Red Cross
Blood Service, South Australia; and Haematology, Institute of
Medical and Veterinary Science; both of Adelaide, Australia; Bone
Marrow Transplant Programme, Alfred Hospital, Melbourne, Australia;
Bone Marrow Transplant Service, Department of Clinical Haematology and
Medical Oncology, Royal Melbourne Hospital; and Victorian
Transplantation and Immunogenetic Service, Australian Red Cross Blood
Service Victoria; both of Parkville, Australia.
Life-threatening complications such as graft versus host disease
and infection remain major barriers to the success of allogeneic hemopoietic stem cell transplantation (SCT). While pretransplantation conditioning and posttransplantation immunosuppression are important risk factors for infection, the reasons that similarly immunosuppressed transplant recipients show marked variation in frequency of infection after allogeneic SCT are unclear. Mannose-binding lectin (MBL) deficiency is a risk factor for infection in other situations where
immunity is compromised. We investigated associations between MBL2 gene polymorphisms and risk of major infection
following allogeneic SCT. Ninety-seven related allogeneic
donor-recipient pairs were studied. Clinical data including survival,
days of fever, graft versus host disease incidence and severity, and
infection were collected by case note review. Five single-nucleotide
polymorphisms in the MBL2 gene were genotyped using the
polymerase chain reaction and sequence-specific primers.
MBL2 coding mutations were associated with an increased
risk of major infection following transplantation. This association was
seen for donor (P = .002, odds ratio [OR] 4.1) and
recipient (P = .04, OR 2.6) MBL2 genotype.
MBL2 promoter variants were also associated with major
infection. The high-producing haplotype HYA was associated
with a markedly reduced risk of infection (recipient HYA
P = .0001, OR 0.16; donor HYA P = .001, OR
0.23). Donor MBL2 coding mutations and recipient
HYA haplotype were independently associated with infection
in multivariate analysis. These results suggest that MBL2
genotype influences the risk of infection following allogeneic SCT and
that both donor and recipient MBL2 genotype are important.
These findings raise the possibility that MBL replacement therapy may
be useful following transplantation.
(Blood. 2002;99:3524-3529) Allogeneic hemopoietic stem cell transplantation
(SCT) is the only curative therapy for a number of malignant and
nonmalignant conditions. However, despite optimal donor-recipient HLA
matching and supportive care, the success of this procedure continues
to be compromised by life-threatening complications such as graft versus host (GVH) disease and infection.1 Factors such as
neutropenia, immunosuppressive agents given as GVH disease prophylaxis,
GVH disease itself, and mucosal breaches from mucositis and
instrumentation are established risk factors for
infection.2 However, the reasons that some allogeneic SCT
recipients develop major infections and other similarly
immunosuppressed allogeneic SCT recipients do not are unclear. The
integrity of the recipient's innate immune response may be an
important factor. Chemoradiotherapy given as pretransplantation
conditioning ablates the recipient's adaptive immune response and
cellular effectors of innate immune responses such as granulocytes,
macrophages, and natural killer cells. Consequently, at a time of such
profound immunosuppression, it is possible that noncellular innate host
defenses less affected by conditioning will assume greater importance.
Mannose-binding lectin (MBL) is an important component of the innate
immune response and is an attractive candidate for investigation in
this setting. MBL is a member of the collectin family that binds to
repeating carbohydrate moieties on a broad range of bacterial, viral,
fungal, and protozoal pathogens independently of antibody3 and directly or via complement activation opsonizes pathogens for
phagocytosis.4 Human MBL is encoded by the MBL2
gene on chromosome 10 (MBL1 is a
pseudogene).5 Five single-nucleotide polymorphisms
influencing serum MBL levels have been identified.6 Polymorphisms in exon 1 at codons 52 (Arg The aim of this retrospective study was to investigate the relationship
between polymorphisms in the MBL2 gene and the risk of major
infection following allogeneic SCT. MBL2 promoter and exonic
polymorphisms were genotyped in 97 related donor-recipient allogeneic
SCT pairs, for whom comprehensive clinical data were available.
Patient and donors
Mannose-binding lectin genotyping
Statistical analysis Data were managed in Filemaker Pro (FileMaker, Santa Clara, CA). Univariate association analyses between categoric variables were performed using contingency tables and the Fisher exact test. Associations between categoric and continuous variables were analyzed using the Student t test. Multivariate analysis was performed using logistic regression analysis (StatView, SAS, Cary, NC).
Outcome measures Median duration of follow-up was 469 days (range, 9-3742). Overall 1-year survival was 56%, with no significant differences between the transplantation centers. Median time to neutrophil count recovery (defined as > 0.5 × 109/L [500 × 106/L] for 2 consecutive days) was 16 days (range, 7-35). Mean days of fever (defined as temperature above 38°C) was 11 (range, 0-66). Fifty-five recipients experienced a total of 98 episodes of major infection, with a median time to onset of first major infection of 20 days (range, 1-300). A major infection was defined as a microbiologically confirmed systemic, disseminated, invasive, or rapidly progressive infection. A diagnosis of pneumonia required compatible clinical or radiologic findings and identification of a causative organism from sputum, nasopharyngeal aspirates, bronchoscopy, blood, or open/transbronchial lung biopsy. Episodes of infection caused by CMV were included if positive CMV antigen or culture results were deemed clinically significant and treatment was administered. The following were not included as major infective episodes: commonly encountered skin contaminant bacteria (eg, coagulase-negative staphylococci) detected in a single blood culture bottle only when multiple were taken, Clostridium difficile diarrhea, dermatomal varicella zoster reactivation, ocular or labial herpes simplex, nonpneumonic respiratory infections, culture-negative interstitial pneumonitis, and culture-negative fever. Twenty-eight recipients experienced a major infective episode while neutropenic and 36 following neutrophil recovery. Twenty-six recipients experienced multiple infective episodes. Causative agents were bacterial in 52 patients, viral in 21 patients, and fungal (not including Pneumocystis carinii) in 7. A breakdown of causative agents and number of infective episodes is provided in Table 1. There was no association between age at or date of transplantation and risk of infection.
MBL2 genotypes Thirty-eight (40.9%) of 93 recipients and 38 (42.2%) of 90 donors carried an MBL2 coding mutation. Promoter and coding haplotype and allele frequencies are listed in Table 2. Observed frequencies did not differ significantly from those predicted by Hardy-Weinberg equilibrium analysis and were in accordance with previously published frequencies.9,10
Mannose-binding lectin polymorphisms and risk of major infection Both MBL2 coding and promoter polymorphisms were associated with risk of infection following transplantation. The presence of a coding mutation (52Cys, 54Asp, or 57Glu) was associated with an increased frequency of major infection. This association was seen when the analysis was performed for donor coding mutations (infection in 76% recipients when donor coding mutation is present vs 44% when no mutation, P = .002, odds ratio [OR] 4.1), recipient coding mutations (68% vs 45%, P = .04, OR 2.6), coding mutations present in either donor or recipient (69% vs 41%, P = .007, OR 3.1), and coding mutations present in both donor and recipient (79% vs 50%, P = 0.01, OR 3.7). These data are summarized in Table 3. The observation of associations between infection and both donor and recipient genotype is not explained by genetic matching: Of the 87 transplantation pairs for whom both donor and recipient genotypes were available, only 38 (43.7%) were MBL2-identical. Furthermore, donor MBL2 coding mutations were associated with infection in both recipients with and without coding mutations, although due to low sample numbers following stratification, P values were of borderline significance. Ten (76.9%) of 13 A/A recipients developed infection when their donor carried a mutation (A/O or O/O), compared with 17 (43.6%) of 39 A/A recipients whose donors were also of A/A genotype (P = .06, OR 3.9, 95% confidence interval [CI] 0.98-16.2). Similarly, examining the subgroup of recipients carrying an MBL2 coding mutation (A/O or O/O), 19 (79.2%) of 24 experienced an episode of major infection when their donor carried a mutation, compared with 6 (50%) of 12 whose donor was of wild-type (A/A) genotype (P = .10, OR 3.5, 95% CI 0.86-15.9). While few recipients were homozygous or compound heterozygotes for MBL2 coding mutations, 4 of 5 such recipients experienced a major infective episode, compared with 45% of those without an MBL2 mutation (P = .05, OR 8.4, 95% CI 0.87-76.5).
Data were also analyzed following stratification of infective episodes as occurring before or after neutrophil count recovery. The presence of donor MBL2 coding mutations was associated with infections occurring after neutrophil recovery but not infections prior to neutrophil recovery. Infections occurred after neutrophil recovery in 20 (53%) of 38 recipients whose donor carried a coding mutations, compared with 13 (25%) of 52 recipients whose donor did not carry a coding mutation (P = .007, OR 3.3, 95% CI 1.4-8.2). In contrast, neutropenic infections occurred in 13 (34%) of 38 recipients whose donor carried a mutation, compared with 12 (23%) of 52 without (P = .35, OR 1.7, 95% CI 0.7-4.4). Associations were also observed between MBL2 promoter
polymorphisms and risk of infection. The HYA haplotype was
associated with a significantly lower frequency of major infections
when present in recipients or donors (Table
4). For example, major infection occurred
in 41% of 56 recipients carrying the HYA haplotype, compared with 81% of 37 recipients lacking this haplotype
(P = .0001, OR 0.16). Similar associations were seen with
donor HYA (44% vs 83%, P = .001, OR 0.23).
The associations between recipient HYA and infection were
observed both in recipients carrying a coding mutation (ie,
HYA/O, P = .04, OR 0.23) and recipients with no
coding mutations (HYA/A, P = .001, OR 0.09)
(Table 5). Associations between donor
HYA and infection were also examined following
stratification according to the presence or absence of donor
MBL2 mutations (Table 5). Identical trends to those seen
with recipient HYA were observed but did not reach
significance for HYA/A donors. Furthermore, none of the 5 recipient HYA/HYA homozygotes and only 2 of the 8 donor
HYA/HYA homozygotes experienced a major infection. The LYA and LXA haplotypes were not individually
associated with major infection in either donors or recipients.
MBL2 genotypes were also stratified as "insufficient"
(associated with very low levels of circulating MBL7) or
"sufficient" (Table 2). The presence of
MBL2-insufficient recipient genotypes was significantly
associated with major infection. Thirteen (86.7%) of 15 recipients with an MBL2-insufficient haplotype experienced
an episode of major infection, compared with 40 (51.3%) of 78 recipients with MBL2-sufficient haplotypes
(P = .01, OR 6.2, 95% CI 1.3-29.2). A similar but not significant trend was seen for donor MBL2-insufficient
genotypes (10 [76.9%] of 13 developed infection vs 42 [54.5%] of
77, P = .13, OR 2.8, 95% CI 0.7-10.1).
Stratification according to type of infection showed that
MBL2 coding mutations and the absence of the HYA
haplotype were associated with bacterial infection (Table
6). These associations were independent
of the presence of neutropenia. It was not possible to determine if
MBL2 polymorphisms were also independently associated with
viral infections, because all recipients who experienced an episode of
major viral infection had also experienced an antecedent bacterial
infection. The number of observed fungal infections was inadequate for
meaningful statistical analysis to be performed.
Multivariate analysis was performed by logistic regression to assess the independence of associations between donor and recipient MBL2 variants and infection. Four independent variables (donor and recipient HYA, donor and recipient MBL2 coding mutations) and one outcome variable (major infection) were analyzed. The HYA haplotype in recipients (P = .002, likelihood ratio 0.17, 95% CI 0.06-0.54) and donor MBL2 coding mutation (P = .03, likelihood ratio 2.8, 95% CI 1.2-7.9) were independent risk factors for the development of major infection. Neither donor HYA nor recipient MBL2 coding mutations were significantly associated with major infection in multivariate analysis. Pearson P value for goodness of fit for this logistic regression model was .66. Associations of MBL2 polymorphisms with other outcome measures While the duration of neutropenic fever appeared longer in patients with recipient or donor MBL2 mutations, this trend did not reach significance (11.1 vs 8.5 days for recipient mutations, P = .09). No association between any of the MBL2 alleles and haplotypes and duration of inpatient stay or early death (occurring in the first 30 days) was observed.Associations between MBL2 variants and GVH disease were also examined. Acute GVH disease was graded by standard criteria.20 Eighty-two patients survived to be evaluable for acute GVH disease. Twenty-two (27%) did not develop acute GVH disease, 20 (24%) developed grade I disease, 22 (27%) grade II, 11 (13%) grade III, and 7 (9%) grade IV. The occurrence of multiple major infective episodes was associated with higher grades of acute GVH disease: 17 (42.5%) of 40 recipients who developed grades II-IV acute GVH disease experienced multiple major infections, compared with 5 (11.9%) of 42 patients with no or grade I acute GVH disease (P = .001, OR 5.5, 95% CI 1.8-16.8). There were no associations between any of the MBL2 polymorphisms and acute GVH disease overall, treatment requiring GVH disease (grades II-IV), or severe GVH disease (III-IV). Sixty-nine patients survived beyond 100 days and thus were evaluable for chronic GVH disease by standard criteria.21 Thirty-two did not develop chronic GVH disease, 7 developed limited, and 30 extensive chronic GVH disease. Multiple infections were associated with chronic GVH disease (13 of 37 patients with chronic GVH disease experienced multiple infections vs 4 of 29 without chronic GVH disease, P = .04, OR 3.4, 95% CI 1.0-11.9). In the 65 recipients graded for chronic GVH disease and genotyped for MBL2, the HYA haplotype was associated with chronic GVH disease in univariate analysis: 18 (44%) of 41 HYA-positive recipients developed chronic GVH disease, compared with 17 (71%) of 24 HYA-negative recipients (P = .03, OR 0.32, 95% CI 0.11-0.94). However, only the occurrence of multiple episodes of major infection was independently associated with chronic GVH disease in multivariate analysis (P = .04).
This retrospective study is the first report of a genetic risk factor for major infection following allogeneic hemopoietic SCT. The presence of MBL2 coding mutations was associated with increased risk of major infection, and the HYA haplotype, previously reported to be associated with high MBL levels,7,22 was associated with reduced risk of infection. MBL is known to be an important innate immune defense against a broad array of bacterial, viral, fungal, and protozoal pathogens.3 Consequently, analyses were performed to examine associations between bacterial, viral, and fungal infections in this patient group. There were significant associations between MBL2 coding mutations and the HYA haplotype and risk of bacterial infection. It was not possible to examine viral infections in a discrete analysis because all patients experiencing viral infections had previously had a bacterial infection. The number of patients experiencing invasive fungal infections was too small for a meaningful statistical analysis to be performed. This study extends recent reports of associations of
MBL2 coding mutations and low MBL levels with duration of
fever and burden of infection following conventional-dose
chemotherapy.17,18 There are several important differences
between the present study and those of Peterslund and
Neth.17,18 Both groups examined the relationship
between MBL and infection in patients with a variety of malignancies
following a number of different chemotherapeutic regimens. The unifying
risk factor for infection in these studies was chemotherapy-induced
neutropenia. Patients undergoing allogeneic SCT are at considerably
greater risk for life-threatening infection than those receiving
conventional-dose chemotherapy. Allogeneic SCT recipients receive
myeloablative chemotherapy with its attendant nonhemopoietic toxicities
to the liver, lungs, skin, and gut. Allogeneic SCT recipients also
experience major breaches in physical defenses by indwelling central
venous catheters and mucosal injury from mucositis and GVH disease.
Furthermore, these patients also have profound and prolonged defects in
cellular and humoral immunity and are reliant on the transplanted donor
cells to restore innate and adaptive immunity.23 The study
of Neth et al18 showed an increase in MBL levels in
patients without coding mutations experiencing infection. There was,
however, no analysis of the well-characterized promoter polymorphisms
in this study, and coding mutations did not fully explain the variation
in MBL levels observed. It is known that MBL2 coding region
mutations have a greater effect on basal MBL levels than the promoter
variants.7,8 This may not be the case following high-dose
chemoradiotherapy, when promoter variants such as HYA, which
allow high levels of MBL transcription, may result in high MBL levels
and afford relative protection from infection. MBL is known to be
synthesized by the liver as an acute phase reactant, and the promoter
region of the MBL2 gene contains response elements to
several of the key mediators released during high-dose
chemoradiotherapy, such as interferon- An intriguing finding from this study concerns the role of donor as well as recipient MBL2 genotype. The associations of both donor and recipient genotype with risk of infection raises questions regarding the relative importance of MBL synthesis by donor and recipient following allogeneic SCT. Several observations suggest that both donor and recipient genotype are important. Only 43.7% of donors and recipients shared identical MBL2 genotypes, indicating that the observed associations with both donor and recipient genotype are not solely due to genetic matching. The MBL2 HYA haplotype was associated with infection in recipients with and without coding mutations, showing that the association of HYA was not secondary to linkage disequilibrium between the coding mutations and the promoter variants. Furthermore, donor MBL2 mutations were associated with infection in both recipients with and without coding mutations and also with infection following neutrophil count recovery but not prior to this time. Finally, donor MBL2 coding and recipient HYA genotype were independently associated with infection in multivariate analysis. The association with recipient MBL2 genotype was expected given the current understanding that the predominant site of MBL synthesis during the acute phase response is the liver.24-27 However, functional studies examining nonhepatic sites of MBL synthesis in humans are very limited. The association between donor genotype and infection following neutrophil count recovery suggests that lymphocytes, macrophages, dendritic cells, or the progeny of hemopoietic stem cells in the donor graft may synthesize MBL in amounts sufficient to influence susceptibility to infection. While functional data in humans are lacking, recent evidence has shown that MBL-C, the murine homolog of human MBL2, is expressed by lymphocytes.28 It is also possible that the association between donor genotype and infection is secondary to linkage disequilibrium with other as-yet-unidentified immunoregulatory genes or that donor MBL levels prior to stem cell harvest influence the donor immune repertoire. However, our results and these preliminary murine functional data suggest that nonhepatic sites of MBL synthesis may be important in vivo. Further studies of MBL2 genotype, synthesis, and kinetics after transplantation are warranted. Acute GVH disease is another frequently lethal complication of allogeneic SCT and has been described as an exaggerated response to infection.29 Furthermore, other triggers of the innate immune response, such as lipopolysaccharide, have emerged as key mediators and targets for intervention in GVH disease.29,30 Consequently, it was of interest to examine associations between MBL2 polymorphisms and incidence of GVH disease. While the presence of multiple major infective episodes was significantly associated with higher grades of acute GVH disease, no associations or trends between MBL2 coding or promoter polymorphisms and acute GVH disease were observed. Recipient HYA was associated with chronic GVH disease in univariate analysis but was not independently associated in multivariate analysis. Thus, while the innate immune response has been implicated in GVH disease pathogenesis in other studies,29,30 there is no evidence from our data that MBL has a role in the pathogenesis of this complication. There is considerable interest in the role of purified or recombinant MBL as a potential therapeutic agent.31-33 Early data suggest that administration of purified MBL is safe and may be effective in ameliorating infection frequency in MBL-deficient individuals.31 Intensive antimicrobial treatment for infection after SCT is often toxic or unsuccessful, and existing strategies to prevent infection such as prophylactic antimicrobials and intravenous immunoglobulin (which contains no MBL) are incompletely effective. Furthermore, the increased susceptibility to infection after allogeneic SCT extends well beyond the initial period of neutropenia, and host immune competence may never be fully regained.34 Thus, if MBL deficiency is confirmed by future genetic and functional studies to be a major risk factor for infection after SCT, this clinical setting would be an ideal scenario for a clinical trial of MBL replacement therapy.
The authors thank Jenny Muirhead and Rosemary Hoyt for assistance with data collection.
Submitted September 20, 2001; accepted January 10, 2002.
Supported by research funding from the Anti-Cancer Foundation of South Australia to C.M., A.G., A.S., J.S., and P.B.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Charles G. Mullighan, Division of Haematology, Institute of Medical and Veterinary Science, PO Box 14, Rundle Mall, Adelaide, SA 5000; Australia; e-mail: cmull{at}senet.com.au.
1.
Bensinger WI, Martin PJ, Storer B, et al.
Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers.
N Engl J Med.
2001;344:175-181 2. Wingard JR. Bacterial infections. In: Thomas ED,Blume KG,Forman KG, eds. Hematopoietic cell transplantation. 2nd ed. Malden, MA: Blackwell Science; 1999:537-549.
3.
Neth O, Jack DL, Dodds AW, Holzel H, Klein NJ, Turner MW.
Mannose-binding lectin binds to a range of clinically relevant microorganisms and promotes complement deposition.
Infect Immun.
2000;68:688-693 4. Turner MW. Mannose-binding lectin: the pluripotent molecule of the innate immune system. Immunol Today. 1996;17:532-540[CrossRef][Medline] [Order article via Infotrieve].
5.
Sastry K, Herman GA, Day L, et al.
The human mannose-binding protein gene. Exon structure reveals its evolutionary relationship to a human pulmonary surfactant gene and localization to chromosome 10.
J Exp Med.
1989;170:1175-1189 6. Turner MW. Mannose-binding lectin (MBL) in health and disease. Immunobiology. 1998;199:327-339[Medline] [Order article via Infotrieve]. 7. Madsen HO, Garred P, Thiel S, et al. Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein. J Immunol. 1995;155:3013-3020[Abstract]. 8. Steffensen R, Thiel S, Varming K, Jersild C, Jensenius JC. Detection of structural gene mutations and promoter polymorphisms in the mannan-binding lectin (MBL) gene by polymerase chain reaction with sequence-specific primers. J Immunol Methods. 2000;241:33-42[CrossRef][Medline] [Order article via Infotrieve]. 9. Mead R, Jack D, Pembrey M, Tyfield L, Turner M. Mannose-binding lectin alleles in a prospectively recruited UK population. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Lancet. 1997;349:1669-1670[CrossRef][Medline] [Order article via Infotrieve]. 10. Mullighan CG, Marshall SE, Welsh KI. Mannose binding lectin polymorphisms are associated with early age of disease onset and autoimmunity in common variable immunodeficiency. Scand J Immunol. 2000;51:111-122[CrossRef][Medline] [Order article via Infotrieve]. 11. Sumiya M, Super M, Tabona P, et al. Molecular basis of opsonic defect in immunodeficient children. Lancet. 1991;337:1569-1570[CrossRef][Medline] [Order article via Infotrieve].
12.
Summerfield JA, Sumiya M, Levin M, Turner MW.
Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series.
BMJ.
1997;314:1229-1232
13.
Koch A, Melbye M, Sorensen P, et al.
Acute respiratory tract infections and mannose-binding lectin insufficiency during early childhood.
JAMA.
2001;285:1316-1321 14. Foster CB, Lehrnbecher T, Mol F, et al. Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease. J Clin Invest. 1998;102:2146-2155[Medline] [Order article via Infotrieve].
15.
Gabolde M, Guilloud-Bataille M, Feingold J, Besmond C.
Association of variant alleles of mannose binding lectin with severity of pulmonary disease in cystic fibrosis: cohort study.
BMJ.
1999;319:1166-1167 16. Garred P, Madsen HO, Balslev U, et al. Susceptibility to HIV infection and progression of AIDS in relation to variant alleles of mannose-binding lectin. Lancet. 1997;349:236-240[CrossRef][Medline] [Order article via Infotrieve]. 17. Peterslund NA, Koch C, Jensenius J, Thiel S. Associations between deficiency of mannose-binding lectin and severe infections after chemotherapy. Lancet. 2001;358:637-638[CrossRef][Medline] [Order article via Infotrieve]. 18. Neth O, Hann I, Turner MW, Klein NJ. Deficiency of mannose-binding lectin and burden of infection in children with malignancy: a prospective study. Lancet. 2001;358:614-618[CrossRef][Medline] [Order article via Infotrieve]. 19. Storb R, Deeg HJ, Whitehead J, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med. 1986;314:729-735[Abstract]. 20. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825-828[Medline] [Order article via Infotrieve]. 21. Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204-217[CrossRef][Medline] [Order article via Infotrieve]. 22. Crosdale DJ, Ollier WE, Thomson W, et al. Mannose binding lectin (MBL) genotype distributions with relation to serum levels in UK Caucasoids. Eur J Immunogenet. 2000;27:111-117[CrossRef][Medline] [Order article via Infotrieve]. 23. Brown JM, Weissman IL, Shizuru JA. Immunity to infections following hematopoietic cell transplantation. Curr Opin Immunol. 2001;13:451-457[CrossRef][Medline] [Order article via Infotrieve]. 24. Wild J, Robinson D, Winchester B. Isolation of mannose-binding proteins from human and rat liver. Biochem J. 1983;210:167-174[Medline] [Order article via Infotrieve]. 25. Summerfield JA, Taylor ME. Mannose-binding proteins in human serum: identification of mannose-specific immunoglobulins and a calcium-dependent lectin, of broader carbohydrate specificity, secreted by hepatocytes. Biochim Biophys Acta. 1986;883:197-206[Medline] [Order article via Infotrieve].
26.
Ezekowitz RA, Day LE, Herman GA.
A human mannose-binding protein is an acute-phase reactant that shares sequence homology with other vertebrate lectins.
J Exp Med.
1988;167:1034-1046
27.
Arai T, Tabona P, Summerfield JA.
Human mannose-binding protein gene is regulated by interleukins, dexamethasone, and heat shock.
Q J Med.
1993;86:575-582 28. Wagner S, Walter W, Loos M. Differential expression of murine MBL-A and MBL-C in B cells, dendritic cells and macrophages by immunoregulatory and proinflammatory cytokines [abstract]. Mol Immunol. 2001;38:126-127. 29. Ferrara JL. Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. J Hematother Stem Cell Res. 2000;9:299-306[CrossRef][Medline] [Order article via Infotrieve]. 30. Cooke KR, Gerbitz A, Crawford JM, et al. LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J Clin Invest. 2001;107:1581-1589[Medline] [Order article via Infotrieve]. 31. Valdimarsson H, Stefansson M, Vikingsdottir T, et al. Reconstitution of opsonizing activity by infusion of mannan-binding lectin (MBL) to MBL-deficient humans. Scand J Immunol. 1998;48:116-123[CrossRef][Medline] [Order article via Infotrieve]. 32. Ohtani K, Suzuki Y, Eda S, et al. High-level and effective production of human mannan-binding lectin (MBL) in Chinese hamster ovary (CHO) cells. J Immunol Methods. 1999;222:135-144[CrossRef][Medline] [Order article via Infotrieve]. 33. Vorup-Jensen T, Sorensen ES, Jensen UB, et al. Recombinant expression of human mannan-binding lectin. Int Immunopharmacol. 2001;1:677-687[CrossRef][Medline] [Order article via Infotrieve]. 34. Martinez C, Urbano-Ispizua A, Rovira M, Carreras E, Rozman C, Montserrat E. Immune reconstitution following allogeneic peripheral blood progenitor cell transplantation. Leuk Lymphoma. 2000;37:535-542[Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
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  J. L. Espinoza, A. Takami, M. Onizuka, H. Sao, H. Akiyama, K. Miyamura, S. Okamoto, M. Inoue, Y. Kanda, S. Ohtake, et al. NKG2D gene polymorphism has a significant impact on transplant outcomes after HLA-fully-matched unrelated bone marrow transplantation for standard risk hematologic malignancies Haematologica, October 1, 2009; 94(10): 1427 - 1434. [Abstract] [Full Text] [PDF]
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 |
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 N. Brouwer, F. N. J. Frakking, M. D. van de Wetering, M. van Houdt, M. Hart, I. K. Budde, P. F. W. Strengers, I. Laursen, G. Houen, D. Roos, et al. Mannose-Binding Lectin (MBL) Substitution: Recovery of Opsonic Function In Vivo Lags behind MBL Serum Levels J. Immunol., September 1, 2009; 183(5): 3496 - 3504. [Abstract] [Full Text] [PDF]
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 R. A. Matthijsen, M. P.J. de Winther, D. Kuipers, I. van der Made, C. Weber, M. V. Herias, M. J.J. Gijbels, and W. A. Buurman Macrophage-Specific Expression of Mannose-Binding Lectin Controls Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Circulation, April 28, 2009; 119(16): 2188 - 2195. [Abstract] [Full Text] [PDF]
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 M. Ramos-Casals, P. Brito-Zeron, N. Soria, N. Nardi, A. Vargas, S. Munoz, A. Bove, B. Suarez, and F. Lozano Mannose-binding lectin-low genotypes are associated with milder systemic and immunological disease expression in primary Sjogren's syndrome Rheumatology, January 1, 2009; 48(1): 65 - 69. [Abstract] [Full Text] [PDF]
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 H. Endeman, B. L. Herpers, B. A. W. de Jong, G. P. Voorn, J. C. Grutters, H. van Velzen-Blad, and D. H. Biesma Mannose-Binding Lectin Genotypes in Susceptibility to Community-Acquired Pneumonia Chest, December 1, 2008; 134(6): 1135 - 1140. [Abstract] [Full Text] [PDF]
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 D J Unsworth Complement deficiency and disease J. Clin. Pathol., September 1, 2008; 61(9): 1013 - 1017. [Abstract] [Full Text] [PDF]
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 C. G. Mullighan, S. L. Heatley, S. Danner, M. M. Dean, K. Doherty, U. Hahn, K. F. Bradstock, R. Minchinton, A. P. Schwarer, J. Szer, et al. Mannose-binding lectin status is associated with risk of major infection following myeloablative sibling allogeneic hematopoietic stem cell transplantation Blood, September 1, 2008; 112(5): 2120 - 2128. [Abstract] [Full Text] [PDF]
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 Y. Liu, Y. Fukuwatari, K. Okumura, K. Takeda, K.-i. Ishibashi, M. Furukawa, N. Ohno, K. Mori, M. Gao, and M. Motoi Immunomodulating Activity of Agaricus brasiliensis KA21 in Mice and in Human Volunteers Evid. Based Complement. Altern. Med., June 1, 2008; 5(2): 205 - 219. [Abstract] [Full Text] [PDF]
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 S. P. Berger, A. Roos, M. J.K. Mallat, A. F.M. Schaapherder, I. I. Doxiadis, C. van Kooten, F. W. Dekker, M. R. Daha, and J. W. de Fijter Low Pretransplantation Mannose-Binding Lectin Levels Predict Superior Patient and Graft Survival after Simultaneous Pancreas-Kidney Transplantation J. Am. Soc. Nephrol., August 1, 2007; 18(8): 2416 - 2422. [Abstract] [Full Text] [PDF]
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K.-H. Lee, S. S. Park, I. Kim, J. H. Kim, E. K. Ra, S.-S. Yoon, Y.-C. Hong, S. Park, and B. K. Kim P2X7 receptor polymorphism and clinical outcomes in HLA-matched sibling allogeneic hematopoietic stem cell transplantation Haematologica, May 1, 2007; 92(5): 651 - 657. [Abstract] [Full Text] [PDF]
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A. Mullally and J. Ritz Beyond HLA: the significance of genomic variation for allogeneic hematopoietic stem cell transplantation Blood, February 15, 2007; 109(4): 1355 - 1362. [Abstract] [Full Text] [PDF]
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J. Font, M. Ramos-Casals, P. Brito-Zeron, N. Nardi, A. Ibanez, B. Suarez, S. Jimenez, D. Tassies, A. Garcia-Criado, E. Ros, et al. Association of mannose-binding lectin gene polymorphisms with antiphospholipid syndrome, cardiovascular disease and chronic damage in patients with systemic lupus erythematosus Rheumatology, January 1, 2007; 46(1): 76 - 80. [Abstract] [Full Text] [PDF]
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M. Moller-Kristensen, W. K. E. Ip, L. Shi, L. D. Gowda, M. R. Hamblin, S. Thiel, J. Chr. Jensenius, R. A. B. Ezekowitz, and K. Takahashi Deficiency of Mannose-Binding Lectin Greatly Increases Susceptibility to Postburn Infection with Pseudomonas aeruginosa J. Immunol., February 1, 2006; 176(3): 1769 - 1775. [Abstract] [Full Text] [PDF]
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M. M. Wurfel, W. Y. Park, F. Radella, J. Ruzinski, A. Sandstrom, J. Strout, R. E. Bumgarner, and T. R. Martin Identification of High and Low Responders to Lipopolysaccharide in Normal Subjects: An Unbiased Approach to Identify Modulators of Innate Immunity J. Immunol., August 15, 2005; 175(4): 2570 - 2578. [Abstract] [Full Text] [PDF]
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 J.-L. Casanova and L. Abel Human Mannose-binding Lectin in Immunity: Friend, Foe, or Both? J. Exp. Med., May 17, 2004; 199(10): 1295 - 1299. [Abstract] [Full Text] [PDF]
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L. Shi, K. Takahashi, J. Dundee, S. Shahroor-Karni, S. Thiel, J. C. Jensenius, F. Gad, M. R. Hamblin, K. N. Sastry, and R. A. B. Ezekowitz Mannose-binding Lectin-deficient Mice Are Susceptible to Infection with Staphylococcus aureus J. Exp. Med., May 17, 2004; 199(10): 1379 - 1390. [Abstract] [Full Text] [PDF]
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A N Tacx, A B J Groeneveld, M H Hart, L A Aarden, and C E Hack Mannan binding lectin in febrile adults: no correlation with microbial infection and complement activation J. Clin. Pathol., December 1, 2003; 56(12): 956 - 959. [Abstract] [Full Text] [PDF]
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 A. J. Barrett, K. Rezvani, S. Solomon, A. M. Dickinson, X. N. Wang, G. Stark, H. Cullup, M. Jarvis, P. G. Middleton, and N. Chao New Developments in Allotransplant Immunology Hematology, January 1, 2003; 2003(1): 350 - 371. [Abstract] [Full Text] [PDF]
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V. Rocha, R. F. Franco, R. Porcher, H. Bittencourt, W. A. Silva Jr, A. Latouche, A. Devergie, H. Esperou, P. Ribaud, G. Socie, et al. Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation Blood, December 1, 2002; 100(12): 3908 - 3918. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
Cys, allele
"D"), 54 (Gly
550g/c
(alleles named H/L) and 
and
interleukin-2.