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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2002-01-0265.
IMMUNOBIOLOGY
From the Department of Hematology and Oncology,
Institute for Medical Information Processing,
Eberhard-Karls-Universität Tübingen, Tübingen,
Germany; Section of Molecular Pathology, Department of
Pathology, Albert-Ludwigs-Universität, Freiburg,
Germany; Institut Pasteur, Paris, France; and
Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne,
Switzerland.
Invasive aspergillosis has become a major cause of
infection-related mortality in nonneutropenic patients after allogeneic stem cell transplantation (SCT). To assess the potential role of
Aspergillus-specific T-cell responses for the successful
control of invasive aspergillosis, lymphoproliferative responses to
Aspergillus fumigatus antigens were studied in
healthy individuals, patients with evidence of invasive aspergillosis,
and patients late after allogeneic SCT. In healthy individuals, a
positive lymphoproliferative response was documented to cellular
extracts of A fumigatus (14 of 16), the 88-kDa
dipeptidylpeptidase (4 of 16), and the 90-kDa catalase (8 of 11). A
predominant release of interferon Invasive aspergillosis has become a major cause of
infection-related mortality in patients with hematologic malignancies, especially after allogeneic stem cell transplantation
(SCT).1 In the immunocompromised patient, invasive
aspergillosis most frequently affects the lungs and is characterized by
hyphal invasion and destruction of pulmonary tissue. Proven risk
factors in humans are defects in phagocyte function,2
steroid-induced suppression of macrophage conidiocidal
activity,3 and chemotherapy-induced neutropenia.4 More recently, invasive aspergillosis has
been reported with an increasing frequency in nonneutropenic patients with advanced AIDS,5,6 in preterm neonates,7
and in patients after solid organ transplantation and allogeneic
SCT.1
Airborne transmission of fungal spores has been considered to be the
major route of transmission of invasive aspergillosis in the
immunosuppressed host. Patients with a previous history of invasive
aspergillosis have been found to be at an increased risk for recurrence
of invasive aspergillosis during a subsequent episode of neutropenia or
immunosuppression.8 These data and results from our group
demonstrating Aspergillus DNA in lower respiratory tract
samples to be an important risk factor for the development of invasive
aspergillosis during a subsequent episode of immunosuppression indicate
that a subset of patients is obviously colonized without signs of
tissue-invasive disease.9 These observations imply that
local cellular defects in the innate and adaptive immune effector
mechanisms are major predisposing factors of the host to invasive
aspergillosis.3,10,11
In the murine model of invasive pulmonary aspergillosis, resistance to
the infection was associated with production of tumor necrosis factor
In the study reported, we assessed the lymphoproliferative T-cell
response to various A fumigatus antigens in healthy
individuals, patients with evidence of invasive aspergillosis, and
patients late after allogeneic SCT. In the vast majority of healthy
individuals and in patients surviving invasive aspergillosis, a
significant lymphoproliferative response to A fumigatus
proteins was found with a dominant release of IFN- Cell preparation
A fumigatus antigens
Conidia of A fumigatus were harvested after 3 days of
culture on Sabouraud dextrose agar (Difco, Detroit, MI), filtered
through sterile gauze, killed by heating in a water bath at 100°C for 1 hour, washed with saline solution, and stored at The 2 major antigens of A fumigatus, the monomeric 88-kDa dipeptidylpeptidase V (DPP V) and the 360-kDa catalase, a tetrameric protein with 90-kDa subunits, were expressed as recombinant proteins in Pichia pastoris and used for T-cell stimulation.16,17 Lymphoproliferation assay The proliferation assay was performed as described before.18 The A fumigatus antigens were added to the wells in concentrations ranging from 50 µg to 50 ng protein/mL. Conidia were tested in lymphoproliferative assays at concentrations ranging from 5 × 105 to 5 × 102. Tetanus toxoid (Chiron Behring, Marburg, Germany), cytomegalovirus (CMV) antigen (Biodesign, Dunn, Asbach, Germany), phytohemagglutinin (PHA; Murex, Life Technology, Karlsruhe, Germany), and IL-2 (Biotest, Dreieich, Germany) were used as control T-cell stimuli and added at final concentrations of 20 µg/mL, 500 ng/mL, 10 ng/mL, and 50 U/mL, respectively. T cells were stimulated with antigen for 5 days and 1 µCi (37 KBq) 3H-thymidine was added overnight. An SI of 3 or higher was considered to indicate a positive lymphoproliferative response.MACS For magnetic-activated cell sorting (MACS) separation (Miltenyi Biotec, Bergisch Gladbach, Germany), isolated mononuclear cells (MNCs) from anticoagulated human blood were labeled with MACS CD4 or CD8 MicroBeads, incubated for 15 minutes at 8°C, and washed extensively. Thereafter, cell suspensions were passed through a positive selection column type MS+ that was placed in the magnetic field of a MiniMACS separator. After removal of the column from the magnetic field, the magnetically retained CD4+ or CD8+ cells could be eluted as a positively selected cell fraction. The unlabeled cell fraction was depleted of CD4+ and CD8+ cells.Cytokine determination PBMNCs (105/200 µL), A fumigatus antigen EC SAB (5µg/mL), or the 90-kDa catalase (5 µg/mL) were cultured in 96-well, round-bottomed plates. After 5 days of culture, the supernatant was removed from each well and stored at 80°C.
Supernatants were tested for IL-10 and IFN- by use of commercial
antigen-capture enzyme-linked immunosorbent assay (ELISA) kits (IL-10
ELISA, DPC Biermann, Bad Nauheim, Germany; IFN- ELISA, Biozol
Diagnostica, Echingen, Germany). In case of cytokine
concentrations below the analytical sensitivity of the assay, a
concentration of 1 pg/mL for the respective cytokines was used to
calculate the IFN-/IL-10 ratio.
TNF bioassay To assess nonpeptide-specific T-cell reactivities of well-characterized V9/V 2 phosphoantigen-reactive T-cell
clones,19 a TNF bioassay was performed as described
previously using the ultrasensitive WEHI-164 clone 13.20
The WEHI cells were grown in complete medium supplemented with 5% FCS
(Gibco). All assays were calibrated with recombinant human TNF.
Patients The Aspergillus-specific T-cell reactivities were assessed in healthy adults and in patients with clinical evidence of invasive aspergillosis after dose-intensive induction/consolidation chemotherapy for acute myeloid (n = 8) and acute lymphoblastic leukemia (n = 4), as well as in patients after allogeneic peripheral blood SCT from matched sibling donors (n = 4) and after bone marrow transplantation from a matched unrelated donor (n = 4; Table 1). The median age in patients treated with chemotherapy only was 46 years (range, 29-67 years) and in patients after allogeneic SCT, 35.5 years (range, 26-48 years). Myeloablative conditioning therapy prior to allogeneic SCT consisted either of fractionated total body irradiation (12 Gy) or busulfan (16 mg/kg body weight [bw]), both in combination with cyclophosphamide (120 mg/kg bw). Patients with high-risk leukemia were additionally treated with etoposide (40 mg/kg bw) or cytosinarabinoside (2 × 2g/m2 on 2 successive days). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A according to serum levels and antithymocyte globulin for 3 days at 20 mg/kg bw on days4 to 2 in patients receiving a transplant from a matched
sibling donor, or for 4 days (4 to 1) in patients receiving a
transplant from a matched unrelated donor.
To compare the immune reconstitution to fungal, bacterial, and viral
antigens late after allogeneic SCT, blood samples from 18 patients
taken at a median of 134 days (range, 86-468 days) after
transplantation were analyzed. Patients characteristics are shown in
detail in Table 2. This time point was
selected, as according to our previous findings, CMV-specific
lymphoproliferative responses can be demonstrated in the majority of
patients at around day 100 after transplantation.18 All
patients gave informed consent to donate blood for immune
reconstitution studies.
Definition of invasive aspergillosis Invasive aspergillosis was categorized according to consensus criteria recently published by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC/IFICG) and the National Institute of Allergy and Infectious Diseases/Mycoses Study Group (NIAID/MSG).21A diagnosis of a proven invasive aspergillosis required histologic proof of a mold infection or a positive culture (or both) obtained by a sterile procedure from a normally sterile and clinically or radiologically abnormal site consistent with infection. Diagnosis of probable invasive aspergillosis required at least one defined host factor (neutropenia < 500/µL for > 10 days, fever for > 96 hours refractory to broad-spectrum antibiotics, signs and symptoms of GVHD, or prolonged use of corticosteroids), and at least one microbiologic (positive culture from sputum or bronchoalveolar lavage fluid, positive cytology or microscopy from a sinus aspirate) and major clinical criterion (new pulmonary infiltrates, halo sign, air-crescent sign, suggestive radiologic findings for an invasive sinus or central nervous system infection). Possible invasive aspergillosis was defined as at least one criterion from the host section and one microbiologic or one major clinical criterion from an abnormal site consistent with infection. According to the state of the lung infiltrates in the computed tomography (CT) scan at the time of blood sampling, patients were classified as having "regression" of invasive aspergillosis if the lesions were smaller compared to previous CT scans, "stable" if there was no difference in the extent of disease manifestations at both dates of examination, or "progression" if the manifestations became worse compared to the preceding assessment. Statistical analysis All observed variables were markedly nonnormally distributed and therefore described with their median and ranges. Wilcoxon signed ranks tests for dependent variables were applied to compare the stimulation indices of the best concentration of EC SAB for lymphoproliferation with the stimulation indices of the other EC SAB concentrations assessed in healthy volunteers. Mann-Whitney U tests were conducted to compare the distributions of the variables between patients with progressive clinical manifestations of invasive aspergillosis and patients with clinical response on antifungal treatment. Spearman rank order correlation coefficients were computed to describe association between Aspergillus-specific lymphoproliferation and neutrophil counts and steroid doses and between steroid doses and IFN- and IL-10 release in culture supernatants.
The McNemar tests and sign tests were used to compare the
lymphoproliferative responses after stimulation with CMV, EC SAB, and
tetanus toxoid, and to compare INF-/IL-10 ratios. All statistical
analyses in this study were done for descriptive purposes without
prestated hypotheses. Test results were presented with nominal 2-tailed P values. All analyses were carried out with JMP version
3.1.6.2 and SAS system for Windows 8.0 software (SAS Institute,
Cary, NC).
Lymphoproliferative responses to A fumigatus antigens in healthy individuals MNCs from healthy volunteers (n = 16) were incubated with declining concentrations of A fumigatus total antigenic extract EC SAB ranging from 50 µg to 50 ng equivalent protein/mL. A maximum SI of 3 or higher (median SI, 7.1; range, 2.1- 86.9) was documented in 14 of 16 healthy individuals (87.5%). All healthy individuals demonstrated a significant lymphoproliferation to PHA (median SI, 15.6; range, 4.1-176.5) and tetanus toxoid (median SI, 9.4; range, 3.3-191.6), and 14 of 16 individuals to IL-2 (median SI, 11; range, 2.2-132.5). Lymphocytes stimulated with 5 µg/mL EC SAB antigen demonstrated 3.3-, 1.5-, and 2.5-fold greater proliferation than did those stimulated with 50 µg/mL, 500 ng/mL, or 50 ng/mL (5 versus 50 µg, P < .0001; 5 versus 0.5 µg, P = .013; 5 versus 0.05 µg, P < .0001). On the basis of these results, we selected the 5 µg/mL concentration for all further experiments.The lymphoproliferative capacity of CD4+, CD8+,
and CD4 Lymphoproliferative responses to heat-inactivated conidia were assessed in 8 healthy individuals with 7 of 8 (87.5%) demonstrating a significant lymphoproliferation (median SI, 17.45; range, 1.6-83.1). The best lymphoproliferative response was documented at a concentration of 1 × 105 Aspergillus conidia/mL. As with EC SAB, the stimulation was definitely lower with the highest dose tested. A significant lymphoproliferative response to the recombinant antigens
was documented in 8 of 11 healthy individuals after stimulation with
the 90-kDa catalase, and in 4 of 16 individuals in response to the
88-kDa DPP V (Figure 1).
Cytokine secretion in culture supernatants of healthy individuals PBMNCs from 17 healthy individuals were stimulated for 5 days with the A fumigatus antigen EC SAB at a concentration of 5 µg/mL, and with the 90-kDa catalase in 11 of these 17 individuals.The baseline IFN- After stimulation of PBMNCs with EC SAB, an increase in the production
of IFN-
V 9/V2 T-cell clones were assessed by a TNF
bioassay. In 6 independent experiments, well-characterized
phosphoantigen-reactive V9/V2 T-cell clones, but not control
 / and control phosphoantigen-nonreactive / T-cell clones,
produced significant quantities of TNF (20-40 pg/mL) to the EC SAB
antigen (dilution 1:40), suggesting that Aspergillus antigen
preparations may contain nonpeptidic antigens (Figure
3).
Aspergillus-specific T-cell responses in patients with clinical evidence of invasive aspergillosis According to the above-mentioned definitions, 5 patients suffered from proven, 3 from probable, and 12 from possible invasive aspergillosis.After stimulation with the whole A fumigatus antigen extract EC SAB, a positive lymphoproliferative response was documented in 14 of 18 patients (median SI, 9.05; range, 1.0-41.4; Table 1). Two additional patients (nos. 7 and 20) not tested with EC SAB showed a positive lymphoproliferative response to an ethanol precipitate of a culture filtrate of A fumigatus (PP EXL) grown in a culture medium containing 1% yeast extract (Difco; SI 3.6 and 13.2, respectively). A positive lymphoproliferative response to PHA was documented in 14 of these 20 patients (median SI, 18.75; range, 0.6-332.1), to tetanus toxoid in 10 of 18 analyzed (median SI, 3.6; range, 0.7-27.2), and to IL-2 in 17 of 20 patients (median SI, 15.95; range, 0.5-201.5). Proven or probable invasive aspergillosis was diagnosed in 5 patients after allogeneic SCT (nos. 1, 2, 6, 7, and 8), and in 3 further patients following intensive chemotherapy for acute myeloid leukemia (nos. 3, 4, and 5) the invasive aspergillosis was proven (Table 1). Six of 7 patients showed a positive lymphoproliferative response to EC SAB and patient no. 7 to the ethanol precipitate. Five of these 8 patients demonstrated at least a partial regression of clinical manifestations of invasive aspergillosis, and patient no. 6 after allogeneic SCT survived cerebral aspergillosis for more than 6 weeks (Table 1). After initial improvement and control of invasive aspergillosis, patients nos. 4 and 5 underwent an allogeneic SCT and subsequently died from disseminated invasive aspergillosis. Another 12 patients with possible invasive aspergillosis according to the above-mentioned definitions were analyzed and 8 of 11 showed an SI more than or equal to 3 in response to EC SAB and patient no. 20 after stimulation with the ethanol precipitate (Table 1). A low SI in response to the EC SAB antigen was demonstrated in 3 of 6 patients after allogeneic SCT with progressive disease (Table 1, patients nos. 9, 10, and 11). The release of IFN-
The correlation of the clinical response at the time of analysis
revealed Aspergillus-specific lymphoproliferation to be
correlated with the neutrophil count (R = 0.459;
P = .064) and to be inversely correlated with the steroid
dose (R = Comparative analysis of lymphoproliferative responses to A fumigatus, tetanus toxoid, and CMV in patients late after allogeneic SCT To compare the immune reconstitution to fungal, bacterial, and viral antigens in patients after allogeneic SCT, blood samples from 18 patients taken at a median of 134 days (range, 86-468 days) after SCT were analyzed. This time point was selected because, according to our previous results, CMV-specific T-cell reconstitution can be demonstrated in the majority of patients at around day 100 after transplantation.A positive lymphoproliferative response was documented in 11 of 14 patients
The cytokine concentrations of IFN-
In the last 1 to 2 decades, an important change in the epidemiology of invasive aspergillosis was observed. Whereas in earlier years, this devastating disease was almost always observed in hematologic patients with long-lasting neutropenia, invasive aspergillosis was reported more recently with an increasing frequency in nonneutropenic patients after allogeneic SCT,1 in patients with advanced HIV infection,6 and in critically ill neonates.7 Transmission via airborne spores was identified as the major route of infection.22 In some patients, colonization occurs without the development of invasive disease; in others, the infection remains restricted to the lungs or may disseminate to a variety of organs and tissues, and on postmortem analysis, Aspergillus may be documented in almost all tissues.23 The pathophysiology of invasive aspergillosis, especially in nonneutropenic patients, is not completely understood. Recognized risk factors for invasive aspergillosis are defects in phagocyte function,2 corticosteroid-induced suppression of phagocyte function,3,24 and long-lasting neutropenia.4 More recently, an increased incidence of invasive fungal infections was observed in patients after allogeneic bone marrow transplantation compared to peripheral blood SCT.25 The only difference between both groups was a faster T-cell reconstitution after transplantation of peripheral blood stem cells indicating a potential role of T cells for the control of fungal infections. Dysregulation of cytokine release has been identified as an important
risk factor in patients with HIV infection.26 In the murine model of invasive pulmonary aspergillosis, resistance to infection was associated with IFN- Based on these clinical observations and experimental results,
Aspergillus-specific T-cell responses were assessed in
healthy individuals, immunosuppressed patients with clinical evidence of invasive aspergillosis, and nonneutropenic patients late (> 100
days) after allogeneic SCT. Almost all healthy individuals demonstrated
a significant lymphoproliferation to cellular extracts of A
fumigatus, heat-inactivated A fumigatus conidia as
reported before,28 and to the 2 major antigens of A
fumigatus, the 90-kDa catalase and the 88- kDa DPP V. Assessment
of the IFN- Major risk factors for invasive aspergillosis after allogeneic SCT are
prolonged neutropenia, acute and chronic GVHD, and corticosteroid
treatment.1 In our study, a low lymphoproliferative response to A fumigatus antigens was found to be associated
with corticosteroid treatment, and a low release of IFN- In addition to T-helper cell responses, the release of TNF from In conclusion, the data reported support the hypothesis that in patients with hematologic malignancies, T cells may contribute to the host defense against A fumigatus. In the future, a detailed analysis of Aspergillus-specific T-cell responses may help to develop new antifungal treatment strategies, such as treatment with proinflammatory cytokines, inhibition of IL-10, or the adoptive transfer of Aspergillus-specific TH1 cells in patients after allogeneic SCT.
We thank Prof Dr Hans-Georg Rammensee and Prof Dr Lothar Kanz for helpful discussions and Friederike Frank for technical assistance.
Submitted January 29, 2002; accepted July 17, 2002.
Prepublished online as Blood First Edition Paper, August 1, 2002; DOI 10.1182/blood-2002-01-0265.
Supported by grants from the Federal Ministry of Education and Research (Fö. 01KS9602) and the Interdisciplinary Center of Clinical Research Tübingen (IZKF), project IIC7, and the AG Infektionen in Hämatologie und Onkologie of the Deutsche Gesellschaft für Hämatologie und Onkologie (DGHO).
H.H. and C.B. contributed equally to this work.
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: Holger Hebart, Medizinische Klinik II, Otfried-Müller Str 10, D-72076, Tübingen, Germany; e-mail: hrhebart{at}med.uni-tuebingen.de.
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T. Fukuda, M. Boeckh, R. A. Carter, B. M. Sandmaier, M. B. Maris, D. G. Maloney, P. J. Martin, R. F. Storb, and K. A. Marr Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning Blood, August 1, 2003; 102(3): 827 - 833. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
/CD8
, IFN-
, IL-10; and *, IL-10 concentrations were assessed in
10 of 11 healthy individuals.
, stimulation index;
,
IFN-
,
IL-10.
tested CMV seropositive before transplantation or receiving a
transplant from a CMV-seropositive donor