Original Article
Host-Specific Interleukin-2–Secreting Donor T-Cell Precursors as Predictors of Acute Graft-versus-Host Disease in Bone Marrow Transplantation between HLA-Identical Siblings
N Engl J Med 1992; 327:1613-1617December 3, 1992
- Abstract
- Abstract
Background.
Acute graft-versus-host disease (GVHD) is a serious complication of allogeneic bone marrow transplantation from an HLA-identical sibling. There is no practical test before transplantation that gives sufficient information to predict the degree of allogeneic reactivity between HLA-identical siblings.
Methods.
We determined the frequency with which host-specific interleukin-2—secreting donor T-cell precursors occurred in 16 consecutive pairs of HLA-identical siblings before they underwent marrow grafting. The results were correlated with the development of acute GVHD after transplantation.
Results.
High frequencies of host-specific T-cell precursors (≥1 per 100,000) were detectable before transplantation in eight donors whose siblings later had severe (grade II or III) acute GVHD. Among the donors to eight patients with mild (grade 0 or I) acute GVHD, low frequencies (<1 per 100,000) were found.
Conclusions.
Analysis of the frequency of such cells before transplantation may be a useful predictor of severe acute GVHD in allogeneic bone marrow transplantation between HLA-identical siblings. It is possible that the patients at risk for serious acute GVHD after marrow grafting may benefit from some alternative form of immunosuppressive therapy. (N Engl J Med 1992;327: 1613–7.)
Media in This Article
Figure 1
Simultaneous Frequency Analysis of Host-Reactive, Donor-Reactive (Autoreactive), and Allogeneic-MHC—Reactive Interleukin-2—Secreting Donor T-Cell Precursors before Transplantation into the Siblings of Patients with Grade II or III (○) or Grade 0 or I (●) Acute GVHD.Table 1
Clinical Characteristics of the 16 Pairs of HLA-identical Siblings in the Study Group.Article Activity
- Article
DESPITE improvements in immunosuppressive therapy after transplantation, acute graft-versus-host disease (GVHD), mediated by host-reactive donor T cells in the bone marrow inoculum, remains a major cause of morbidity and mortality after allogeneic bone marrow transplantation between HLA-identical siblings.1 , 2 Although some efforts have been made,3 , 4 there is no practical predictive test to identify patients who are at risk for this serious complication, and thus to identify those who might benefit from T-cell depletion of the marrow graft before transplantation or some alternative form of immunosuppressive therapy.
In transplantations involving HLA-identical siblings, host-reactive donor T cells are by definition directed against minor histocompatibility antigens presented by molecules of the major histocompatibility complex (MHC).5 , 6 From murine models7 8 9 10 and limited data from humans,11 , 12 it has been suggested that lymphokine-secreting donor T cells that are specific for minor histocompatibility antigens help to determine which patients will have acute GVHD.
In the present study, 16 consecutive pairs of HLA-identical siblings who were to undergo allogeneic bone marrow transplantation were analyzed for the presence of host-specific interleukin-2—secreting donor T-cell precursors before transplantation with a limiting-dilution method. The results clearly indicate that high frequencies of host-specific T-cell precursors in the donor before transplantation correlate with the development of severe acute GVHD in the recipient after transplantation.
Methods
Patients
We studied 16 consecutive patients who received marrow grafts that had not been depleted of T cells in the bone marrow transplantation unit of Ulm University Hospital (Ulm, Germany) in 1990 and who survived for at least 100 days after transplantation. The clinical characteristics of the study group are listed in Table 1Table 1
Clinical Characteristics of the 16 Pairs of HLA-identical Siblings in the Study Group.. All 16 patients received cyclosporine and methotrexate after transplantation as immunosuppressive agents for the prevention of GVHD, as previously reported.1 The diagnosis of acute GVHD was established by clinical and histopathological criteria.13 In a retrospective analysis, the HLA-identical sibling donors were evaluated for the presence before transplantation of circulating host-specific interleukin-2—secreting T-cell precursors.HLA Typing
With conventional serotyping of HLA-A, B, C, DR, and DQ alleles, we performed HLA typing of peripheral-blood mononuclear cells and HLA retyping of B-lymphoblastoid cell lines from the sibling pairs and from unrelated healthy volunteers that had been transformed in vitro by Epstein–Barr virus (EBV). Oligonucleotide typing of HLA-DPB1 alleles was also performed,14 because disparate HLA-DP alleles are sometimes expressed by siblings presumed to be HLA-identical.15 All the sibling pairs were negative on the Standard mixed-lymphocyte culture and the lymphocyte cross-match, and they were all genotypically matched for HLA-A, B, C, DR, DQ, and DPB1 alleles (data not shown).
Frequency of Interleukin-2—Secreting T-Cell Precursors
The frequency of interleukin-2—secreting T-cell precursors in the donors was determined by limiting-dilution analysis. Limiting-dilution analysis is a sensitive technique for the quantitative assessment of T-cell functions that are difficult to detect in conventional culture systems.16 , 17 By serial dilution of responder cells and the application of Poisson statistics, one can determine the number or frequency of T-cell precursors with a given function and antigenic specificity.
The methodologic details of limiting-dilution analysis of interleukin-2—secreting T-cell precursors have been reported elsewhere.18 , 19 In brief, various numbers of responding peripheral-blood mononuclear cells obtained from the donor before transplantation were cultured with 1×104 stimulating peripheral-blood mononuclear cells that had been irradiated with 20 Gy and had been obtained from the host or the donor before transplantation or from unrelated, completely HLA-mismatched volunteers. Sixteen replicate microcultures were set up in V-shaped microtiter plates (Nunc, Wiesbaden, Germany). The culture medium was RPMI-1640 (Biochrom, Berlin, Germany), supplemented with a 10 percent (vol/vol) heat-inactivated pooled human AB serum, 25 mmol of HEPES buffer, 2 mmol of L-glutamine, 5×10–5 mol of 2-mercaptoethanol, 100 μg of streptomycin, 100 IU of penicillin, and 10 U of human recombinant interleukin-2 (Eurocetus, Amsterdam) per milliliter. For each pair of siblings, limiting-dilution cultures were set up simultaneously to analyze the frequency of host-reactive, donor-reactive, and allogeneic-MHC—reactive donor T-cell precursors.
After 14 days, the cultures were washed twice with phosphate-buffered saline (GIBCO, Paisley, Scotland), and restimulated with 1×105 EBV-transformed cells, irradiated with 40 Gy, from the primary stimulating host, donor, or HLA-mismatched volunteer. The EBV-transformed cells do not secrete interleukin-2, but they strongly induce the production of interleukin-2 by responder T cells and have therefore been considered essential for restimulation.18 , 19 After 20 to 24 hours, 0.075 ml of supernatant was removed and transferred to flat-bottomed microtiter plates (Nunc) for interleukin-2 analysis.
Clonal Specificity
The clonality of colonies that produce interleukin-2 is defined as their ability to develop from a single T-cell precursor. The probability of clonality can be estimated from the known frequency of precursors by applying Poisson statistics.16
For the analysis of clonal specificity, each limiting-dilution culture was washed twice in phosphate-buffered saline after 14 days, divided into two aliquots, and restimulated with both the primary stimulating antigen from the host and the autologous donor antigen (1×105 irradiated EBV-transformed cells per well) obtained before transplantation.
Interleukin-2 Activity
Interleukin-2 activity was determined by colorimetric bioassay, as described elsewhere.18 , 19 Briefly, 1.5×104 CTLL-16 indicator cells, the growth of which is dependent on interleukin-2 and is not promoted by human interleukin-4,18 , 19 were incubated in a final volume of 0.1 ml. After 20 to 24 hours, 0.01 ml of a solution of 5 mg of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT, Sigma Chemical, St. Louis) per milliliter was added, and 3 hours later, 0.01 ml of 10 percent sodium dodecyl sulfate and 0.01 mol of hydrochloric acid per liter was added to each well to dissolve the blue crystals. After overnight incubation, the optical density of each well was read at 570 nm, with a plate reader (model NJ-2000, Nunc). The maximal MTT cleavage was assessed in two wells containing 20 U of human recombinant interleukin-2 per milliliter. Microcultures were considered positive if the optical density was more than 3 SD above the mean for control cultures containing only stimulator cells.
Statistical Analysis
The calculation of frequencies from limiting-dilution analysis was based on Poisson distribution. The values and 95 percent confidence intervals for the frequency, as well as the probability of single-hit kinetics (the presence or absence of only the cell type being measured), were calculated by likelihood maximization and chi-square minimization as described by Taswell.20 The frequency of interleukin-2—secreting T-cell precursors is shown only if the P value (probability of single-hit kinetics) was >0.05 and the chi-square value <10.20
Results
A high frequency (≥1 per 100,000) of host-reactive interleukin-2—secreting donor T-cell precursors was detectable before transplantation in the siblings of eight patients with severe acute GVHD (grade II or III) after transplantation (Table 2Table 2
Frequency of Host-Reactive Interleukin-2—Secreting Donor T-Cell Precursors before Transplantation and Correlation with Acute GVHD after Transplantation.*). In contrast, among the siblings of eight patients with mild acute GVHD (grade 0 or I), a low frequency (<1 per 100,000) of such T-cell precursors was found (Table 2). The frequency of host-reactive T-cell precursors among the pairs with GVHD of grade II or higher differed from that among the pairs with grade I or lower disease (P<0.001 by the Mann—Whitney U test). High frequencies of host-reactive donor T-cell precursors were significantly correlated with grade II or III acute GVHD, as determined by Fisher's exact test (P<0.001). In all 16 pairs of siblings the frequency of allogeneic-MHC—reactive donor T-cell precursors was greater than the frequency of host-reactive precursors (Fig. 1Figure 1Simultaneous Frequency Analysis of Host-Reactive, Donor-Reactive (Autoreactive), and Allogeneic-MHC—Reactive Interleukin-2—Secreting Donor T-Cell Precursors before Transplantation into the Siblings of Patients with Grade II or III (○) or Grade 0 or I (●) Acute GVHD.). The antigen specificity of host-reactive donor T-cell precursors among patients with grade II or III acute GVHD was indicated by the fact that only low (<1 per 100,000) frequencies of responding precursors were detectable after primary autologous stimulation (Fig. 1). In contrast, among patients with grade 0 or I acute GVHD no difference in the frequency of donor precursor cells was observed after primary induction with autologous donor cells as compared with host stimulator cells (Fig. 1).The antigenic specificity of host-reactive donor T-cell precursors among the pairs of siblings with grade II or III acute GVHD was quantitatively confirmed at the clonal level before transplantation. The relative distribution of host-specific donor T-cell colonies that produced interleukin-2 was therefore evaluated with limiting-dilution split-well cultures that indicated a chance of clonality of more than 70 percent. The results are summarized in Table 3Table 3
Clonal Specificity of Anti-Host Induced Interleukin-2—Secreting Donor T-Cell Precursors before Transplantation.. After restimulation with primary stimulating host antigens and autologous donor antigens in patients with grade II or III acute GVHD, the vast majority (91 percent) of host-reactive donor T-cell colonies that produced interleukin-2 appeared to be specific exclusively for host antigens. In contrast, the majority (79 percent) of anti-host induced donor T-cell colonies among patients with grade 0 or I acute GVHD cross-responded to autologous donor antigens and were therefore attributed to an autologous background response.Discussion
Our study demonstrates a significant correlation between a high frequency of host-specific interleukin-2—secreting donor T-cell precursors before transplantation and the development of severe acute GVHD in bone marrow transplantation between HLA-identical siblings. Other factors, such as the patient's age and a mismatch for sex, were not correlated with the donor T-cell response or the development of acute GVHD. In two of the four donors who had been previously allogeneically sensitized by pregnancy, high frequencies of host-specific T-cell precursors preceded the development of grade II acute GVHD in the recipients (Patients 13 and 14). The involvement of classic sex-chromosome—associated minor histocompatibility antigens, such as the male-specific antigen H-Y,5 must be considered in the case of Patient 14 and his donor, who were mismatched for sex.
No practical test is currently available to identify before transplantation patients who are at risk for serious acute GVHD after marrow grafting from an HLA-identical sibling. Limiting-dilution analysis of host-reactive cytotoxic donor T-cell precursors has been successfully used before transplantation to predict the incidence and severity of acute GVHD in grafting between phenotypically HLA-matched unrelated donors and patients.21 , 22 The assay proved unsuitable for the detection of T-cell responses between HLA-identical siblings, however.21 , 22 It is well established that T-cell responses between HLA-identical siblings are virtually undetectable in standard mixed-lymphocyte culture.23 By modifying the mixed-lymphocyte culture, one can correlate overall donor allogeneic reactivity, although not specificity for host antigens, to some extent with the development of acute GVHD in bone marrow transplantation between HLA-identical siblings.24 , 25 With a more complex and time-consuming in vitro model of donor allogeneic reactivity, the response of host-reactive donor T cells before transplantation has been studied in enough HLA-identical pairs of siblings to predict acute GVHD in subsequent marrow grafting,3 but this assay has not been considered practical for clinical application. Vogelsang et al.4 circumvented the problem of nonresponsiveness between HLA-identical siblings in mixed-lymphocyte culture by sensitizing donor T cells in vitro and then coculturing them with host skin explants. Reactivity was determined by histopathological examination. Although this method has reasonable predictive value, it is laborious, and controls for specificity are particularly cumbersome. Under appropriate culture conditions, skin target cells can be replaced by blood mononuclear cells or by EBV-transformed cells.26 , 27 Limiting-dilution analysis eliminates extensive in vitro priming and allows one to determine the antigenic specificity of responding T cells quantitatively.18 , 19 It proved to be simple, time-saving, sensitive, and specific, and it can therefore be considered a clinically practical assay for the prediction of acute GVHD in bone marrow transplantation between HLA-identical siblings. Further experience will tell.
How do interleukin-2—secreting T cells contribute to the induction of acute GVHD? According to the classic concept of T-cell cooperation, T cells that secrete interleukin-2 are essential for the proliferation and differentiation of activated cytolytic T-cell precursors.7 Apart from the well-established cooperation with cytolytic T lymphocytes, T cells that secrete interleukin-2 may trigger tissue damage in acute GVHD by releasing various other lymphokines, such as tumor necrosis factor α28 29 30 and interferon gamma.31 The involvement of human lymphokine-secreting T cells in the induction of GVHD is also suggested by the recent finding that the detection of host-specific noncytolytic proliferating T cells rather than cytolytic T cells after transplantation correlates with the incidence of severe acute GVHD.11 , 12
In conclusion, analysis of the frequency of host-specific interleukin-2—secreting T-cell precursors before transplantation may allow a more precise prediction of the incidence and severity of acute GVHD after marrow grafting from an HLA-identical sibling. Patients at risk for serious acute GVHD may be identified before transplantation and assigned alternative immunosuppressive regimens, such as selective T-cell depletion32 or treatment with anti—tumor necrosis factor antibody33 or interleukin-1—receptor antagonist.34
Supported by a grant from the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 322/C7).
We are indebted to Gudrun Kepes, Susanne Scherr, and Gaby Schneiderhan for expert technical assistance.
Source Information
From the Bone Marrow Transplantation Unit, Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany. Address reprint requests to Dr. Theobald at the Department of Immunology, Scripps Research Institute, 10666 N. Torrey Pines Rd., La Jolla, CA 92037.
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