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Biomedical subjects

D Dilloo

Publications and source records attributed to D Dilloo.

At least 37 records · Page 2Linked to original sources
PubMed1996

Gene marking and gene therapy for transplantation medicine.

The classic application for gene therapy is in the correction of single gene defects, although this has been complicated by the low efficiency of gene transfer into hematopoietic cells. Gene therapy, however, has potential for the modulation of tumor cell growth, drug sensitivity, and antitumor immune responses. In addition, gene marking can be used, in spite of this limited transfer efficiency, to provide information on hematopoiesis, sources of cancer relapse after stem cell transplant, and the relative efficacy of graft manipulation techniques. This article reviews the applications of gene therapy and gene marking in transplantation medicine.

Biomarkers↗
PubMed1996

Differential production of interleukin-3 in human T lymphocytes following either CD3 or CD2 receptor activation.

Interleukin-3 (IL-3) is expressed in T lymphocytes and stimulates the growth of multipotent hematopoietic progenitors. Little is known, however, about the stimuli that lead to IL-3 protein release. We examined IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA expression and protein secretion in human T lymphocytes following activation via the TCR/CD3 complex, the CD2 receptor, and the IL-2 receptor. GM-CSF mRNA expression and protein release were found in CD3 and CD2 activated T cells with maximum GM-CSF release following stimulation with IL-2. IL-3 protein release is regulated via the CD2 receptor with virtually no IL-3 release after T cell stimulation via CD3. In contrast, IL-3 mRNA accumulation is more pronounced after CD3 activation than after CD2 activation. This suggests that upregulation of IL-3 protein release following T cell stimulation via CD-2 occurs largely at the translational or posttranslational level. These data also indicate that differential control of cytokine production can occur in response to activation of the alternative T cell receptor. Interaction of the T cell CD2-receptor with its natural ligand LFA-3 expressed on stromal cells might represent a regulatory mechanism for rapid release of IL-3, facilitating proliferation of multipotent hematopoietic cells.

CD2 Antigens↗
PubMed1995

Bone marrow fibroblasts from children with aplastic anemia exhibit reduced interleukin-6 production in response to cytokines and viral challenge.

Defects of the bone marrow microenvironment have been implicated in the pathogenesis of aplastic anemia (AA). We examined granulocyte/macrophage colony-stimulating factor (GM-CSF) and IL-6 production in bone marrow fibroblasts from five children with AA in response to cytokines and viral challenge with cytomegalovirus (CMV). Cytokine-stimulated IL-6 production in patients' fibroblasts was significantly reduced, whereas GM-CSF production was found to be comparable to normal controls. Also, CMV-mediated stimulation of IL-6 production was significantly lower in bone marrow fibroblasts from patients with AA. During the late phase of CMV-infection, IL-6 production was suppressed in CMV-infected fibroblasts from patients with AA with 90% inhibition of IL-6 protein production and marked reduction in IL-6 mRNA accumulation. Defective IL-6 production in bone marrow fibroblasts might contribute to hematopoietic suppression in some patients with AA.

Adolescent↗
PubMed1995

IL-2 inhibits proliferation of K562 cells and reduces accumulation of bcr/abl mRNA and oncoprotein.

Cell lines of myeloid origin have been shown to express interleukin-2 receptors (IL-2R). Here, we demonstrate the expression of IL-2R alpha and IL-R beta on the CML blast cell line K562 by FACS analysis and cross-linking assay. Furthermore, we examined the effect of IL-2 on leukemic progenitor growth, employing K562 as a model. Clonogenic growth was assessed after 3 days of culture by colony formation in a serum-free, semi-solid assay system. IL-2 was found to exhibit a dose-dependent suppressive effect on K562 clonogenicity with 48% inhibition of colony formation at 250 U IL-2 and 60% inhibition at 1000 U IL-2. Philadelphia chromosome (Ph)-positive K562 cells possess multiple copies of the bcr/abl fusion gene whose transcript and protein product (p210) is thought to confer growth advantage to CML cells. We therefore investigated IL-2-dependent modulation of bcr/abl mRNA accumulation and p210 protein levels in K562 cells. After 4 h of culture in the presence of IL-2, a 3-15-fold reduction of bcr/abl mRNA accumulation was demonstrated by competitive reverse PCR. Reduction of bcr/abl fusion protein levels was demonstrated at 24 h of IL-2-supplemented cell culture, employing p210 recognizing monoclonal antibodies (mAbs) in FACS analysis. Levels of proliferation marker Ki67 were only marginally affected. We conclude: (1) K562 cells express both IL-2R alpha and IL-R beta; (2) IL-2 inhibits clonogenic growth of K562 in a dose-dependent manner; and (3) IL-2-mediated inhibition of K562 proliferation is preceded by a reduction of bcr/abl mRNA accumulation and p210 protein levels.

Base Sequence↗
PubMed1995

Time course of interferon-gamma production deficiency after autologous and allogeneic stem cell transplantation for malignancies.

While success of autologous bone marrow transplantation (BMT) for malignancies largely depends on the cytotoxicity of the ablative regimen, achievement of relapse-free survival after allogeneic BMT is thought to be enhanced by immunologic effects. We therefore investigated in vivo and in vitro production of interferon-gamma (IFN-gamma), soluble interleukin-2 (IL-2) receptor alpha-chain (sCD25), tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients before and during various time periods up to 2 years after autologous and allogeneic BMT. Cytokine levels were assessed in patient plasma and in supernatants of patient-derived peripheral blood mononuclear cells (PBMNC) cultured for 3 days in the presence of T cell-specific stimulation via CD3 plus IL-2. Our studies show that IFN-gamma plasma levels are decreased in autologous graft recipients before and during the first 30 days posttransplant. In allogeneic graft recipients, IFN-gamma plasma levels are also decreased during the first 30 days posttransplant, but otherwise are comparable to normal control (NC) values. In vitro stimulated PBMNC from autologous graft recipients also exhibit an IFN-gamma production defect before and during the first 30 days posttransplant. In contrast, before and up to 30 days after allogeneic BMT, stimulated IFN-gamma production is comparable to NC values but then gradually decreases, reaching its trough levels at between 61 and 180 days post-BMT. The IFN-gamma production defects in both patient groups seem to be specific, as sCD25, TNF-alpha, and GM-CSF production in stimulated PBMNC is normal or even enhanced at any time after autologous or allogeneic BMT. Deficient IFN-gamma production in patient-derived PBMNC does not correlate with variation in monocyte, T cell, or natural killer (NK) cell numbers during the posttransplantation course.

Adolescent↗
PubMed1994

Induction of two distinct natural killer-cell populations, activated T cells and antineoplastic cytokines, by interleukin-2 therapy in children with solid tumors.

Children with poor prognoses regarding solid tumors have benefited from autologous bone marrow transplantation as a treatment modality. Posttransplantation adjuvant interleukin-2 (IL-2) therapy has previously been shown to improve prognosis in adults with neoplastic disease. The improved survival probability has been attributed to IL-2-mediated stimulation of the immune system and its antineoplastic activity. In this study, 10 pediatric patients with solid tumors in complete remission after autologous stem cell transplantation were treated with recombinant IL-2, which was administered in three 5-day cycles of continuous intravenous infusions with a 2-week rest in between cycles. We demonstrated that IL-2 therapy enhanced transplantation-related stimulation of the immune system, on both the cellular and humoral levels. Peripheral blood T and natural killer (NK) cells increased by the factors four and 14, respectively. Activation of the immune system was demonstrated by significantly elevated levels of soluble IL-2 receptor (IL-2R) and increased CD25 surface expression on T lymphocytes. IL-2 also induced significant proliferation of the CD56bright NK-cell subpopulation that appears post-bone marrow transplant (BMT) and is found only in minimal amounts in normal controls. In vivo and in vitro production of tumor cytotoxic cytokines tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) was significantly stimulated following IL-2 therapy, further indicating IL-2-mediated stimulation of the antineoplastic activity of the immune system.

Adolescent↗
PubMed1993

Myeloablative radiochemotherapy and hematopoietic stem-cell rescue in poor-prognosis Ewing's sarcoma.

PURPOSE: The prognosis of patients with multifocal primary and early or multiple relapsed Ewing's sarcoma is poor with conventional chemoradiotherapy and surgery. We evaluated the efficacy and feasibility of a myeloablative regimen administered as consolidation treatment for these patients. PATIENTS AND METHODS: The ablative regimens consisted of simultaneous radiochemotherapy: 12 Gy hyperfractionated total-body irradiation (TBI; two doses of 1.5 Gy for 4 days) plus fractionated high-dose melphalan (30 to 45 mg/m2 for 4 days) followed by high-dose etoposide (40 to 60 mg/kg) with or without carboplatin (900 to 1,500 mg/m2) (hyper-ME +/- C). These regimens were applied in a dose-escalation study that included 17 patients. All patients underwent remission induction chemotherapy and local treatment before myeloablative therapy. Seven patients had multifocal primary Ewing's sarcoma, and 10 had early or multiple relapse. We performed a matched-cohort analysis of the 17 grafted patients with 41 historic controls matched for sex, age, diagnosis, extent of disease, interval from diagnosis to transplant in the transplant group, and interval from diagnosis to relapse in the control group. RESULTS: The probability of relapse in the study patients is 52% at 6 years after the last event before transplantation. In the control group, the probability of relapse at 6 years was 98%. Eight of 17 treated patients are alive in complete remission at a median observation time of 49 months (range, 19 to 76) from the last event before transplantation. Probability of relapse-free survival in the study patients is 45% +/- 12% at 6 years after the last event before transplant, compared with 2% +/- 2% for the historic control group. CONCLUSION: Myeloblative therapy with hyper-ME +/- C radiochemotherapy can improve the prognosis of multifocal primary and early or multiple relapsing Ewing's sarcoma.

Adolescent↗
PubMed1992

Treatment of donor T cell-mediated hematopoietic suppression after haploidentical bone marrow transplantation by T cell modulation in a patient with severe combined immunodeficiency.

An 8-month-old male patient with severe combined immunodeficiency syndrome was transplanted with maternal, haploidentical T cell-depleted bone marrow without prior conditioning therapy. Acute graft-versus-host disease developed 2 weeks post bone marrow transplantation (BMT) and was successfully treated with cortisone. After cortisone withdrawal the patient developed myeloid and B cell depression concomitant with T cell activation. For specific T cell modulation, treatment with the T cell receptor (TCR) alpha beta chain-binding MoAb BMA031 was initiated in combination with cyclosporin A. GM-CSF was given to enhance myeloid reconstitution. About 1 year post BMT, B cell and granulocyte counts were within the normal range with stable chimerism in both lineages. B cell proliferation tests were normal and first signs of in vitro immunoglobulin synthesis occurred.

Agranulocytosis↗
PubMed1991

Differential regulation of lymphokine production by distinct subunits of the T cell interleukin 2 receptor.

Most biologic responses to IL-2 have been attributed to interaction of IL-2 with a high affinity receptor which consists of a heterodimer composed of two distinct IL-2-binding proteins (IL-2R alpha/IL-2R beta). However, both low affinity IL-2R alpha (55 kD) and intermediate affinity IL-2R beta (70-75 kD) also appear to be expressed independently on the cell surface. We investigated the receptor-specific regulatory effects of IL-2 on cytokine production in unstimulated and activated T cells. T cells were activated by stimulation of the antigen receptor complex with anti-CD3 mAb. IL-2 (10(2) U/ml, 1 nM) stimulation of resting cells resulted in a fivefold increase in GM-CSF release but in only minimal IFN-gamma release. IL-2 markedly augmented mRNA expression of GM-CSF but not IFN-gamma in unstimulated T cells. IL-2R beta mAb but not IL-2R alpha mAb decreased IL-2-induced GM-CSF release and mRNA expression from unstimulated T cells. IL-2 concentrations required for GM-CSF release from resting cells suggested ligand binding to an intermediate affinity receptor. GM-CSF and IFN-gamma release from activated T cells increased four- to fivefold in response to 1 nM IL-2 and IL-2 augmented both GM-CSF and IFN-gamma mRNA. IL-2R beta mAb but not IL-2R alpha mAb reduced GM-CSF release and mRNA expression in activated T cells stimulated with 1 nM IL-2. IL-2R alpha blockade markedly decreased IL-2-induced IFN-gamma release and mRNA expression from activated cells, while IL-2R beta blockade had little effect on IFN-gamma production in activated cells. IL-2R alpha blockade altered the affinity of the receptor mediating activated cell GM-CSF release from a high affinity to an intermediate affinity state. These studies indicate an independent role for IL-2R beta in mediating GM-CSF production from T cells. They also suggest that unstimulated and activated T cells, which express distinct IL-2 receptor moieties, mediate release of separate lymphokines and that different subunits of the IL-2 receptor may play an important role in the regulation of cytokine production.

Antibodies, Monoclonal↗
PubMed1984

Zinc ions are differentially required for the transcription of ribosomal 5S RNA and tRNA in a HeLa-cell extract.

Chelation of divalent cations by 5 mM EDTA and subsequent removal by dialysis from a cytoplasmic HeLa cell extract leads to a complete loss of 5S rRNA transcription without affecting tRNA synthesis. Transcription complexes for 5S RNA can no longer be assembled in such a zinc-depleted extract and this ability can be fully restored only by the re-addition of 5 microM zinc. Reconstitution experiments with isolated protein fractions show that transcription factor A from HeLa-cells requires zinc to exert its specific function. Pre-formation of transcription complexes partially protects the metal ion against removal by chelation even in the presence of 1.8 M KCl. These results indicate that the zinc ions are bound to mammalian transcription factor IIIA which, in a transcription complex, binds very strongly to the 5S RNA gene. Cation depletion with 75 mM EDTA also suppresses tRNA transcription; an effect which is reversible by zinc addition. We conclude that beside for the binding of TF IIIA, zinc is also bound with a different affinity to a transcription component common to 5S and tRNA synthesis, most likely polymerase III itself.

Edetic Acid↗
PubMedDate not supplied

Long-time survival after unrelated bone marrow transplantation in children and adolescents and targeted therapy with CD25 blockade to prevent GVHD.

To evaluate longtime survival after matched unrelated donor (MUD) transplantation a group of patients (n = 10) with intensified GVHD prophylaxis were compared to patients receiving matched sibling (MSD) transplantation (n = 10); all transplantations were done between 1989 and 1995 in the same institution. A murine monoclonal antibody against CD25 was assessed in addition to standard GVHD prophylaxis for reducing GVHD in children with advanced leukemia after MUD BMT (group I). We compared the incidence of GVHD, relapse and survival under prophylaxis with either anti-CD25 (group I, n = 10) or MSD BMT without anti-CD25 (group II, n = 10) with respect to known risk factors of transplant related morbidity, mortality and outcome. 3/10 leukemia patients in both groups were in CR3 or in relapse at time of transplant. Whereas incidence of acute GVHD grade III and IV was significantly higher in group I compared to group II (0.4 vs. 0.0), no differences in engraftment, or chronic GVHD were seen between both groups. In addition, overall (0.5 vs. 0.6) and leukemia free survival (0.5 vs. 0.6) was not different after 8 respectively 10 years from transplant. Murine anti-CD25 therapy may have contributed to matching outcome of MUD vs. MSD marrow transplants in children with advanced leukemia. In conclusion, the use of anti-CD25 in modulation of CD25+ regulatory and effector T cells in allo- and leukemia recognition merrits further exploration of its potential to improve both tolerance and leukemia control. Since the outcome of children with leukemia that received intensified GVHD prophylaxis in MUD BMT was similar to children with MSD transplants, MUD BMT has to be considered as an equivalent therapeutic option for patients, who have no HLA-identical sibling donor.

Acute Disease↗
PubMedDate not supplied

Characterization of CD34+ progenitor-derived dendritic cells pulsed with tumor cell lysate for a vaccination strategy in children with malignant solid tumors and a poor prognosis.

BACKGROUND: Children and adolescents with primary multifocal, refractory or relapsed malignant extracranial solid tumors still have a poor prognosis inspite of intensive standard radio-/chemotherapy. Here complementary immunomodulatory treatment modalities may prove beneficial as consolidation therapy following cytoreduction. Neuroblastoma, Ewing tumor and soft tissue sarcoma cells have principally been shown to be susceptible towards both cytotoxic and humoral effector mechanisms. Yet in vivo they are not capable of inducing an effective antitumor response which has been attributed to low level MHC expression and lack of costimulatory surface molecules. Professional antigen - presenting cells such as dendritic cells (DCs) in contrast are capable of activating unprimed T cells and are therefore ideal tools for vaccine generation. RESULTS: Here we demonstrate that DCs may be generated from CD34+ progenitor cells to clinical scale in a three to four week cell culture process including an initial expansion and subsequent differentiation and maturation steps. DCs derived from CD34+ progenitors express the expected marker profile and are highly effective in stimulating allogeneic T cell effectors. We also demonstrate that they effectively take up fluorescence-labelled tumor cell lysate. DISCUSSION: Having established a cell culture process for clinical scale DC production utilizing CD34+ progenitors as the cellular source we discuss the role of CD34+ derived DCs in clinical vaccination protocols. The rationale for a phase I/II DC dose escalation study for high risk pediatric patients with extracranial solid tumors assessing safety, immunological and clinical efficacy of serial combined intranodal and subcutaneous injections of tumor cell lysate-pulsed autologous DCs is delineated.

Adolescent↗
PubMedDate not supplied

Transplantation of haematopoietic stem cells derived from cord blood, bone marrow or peripheral blood: a single centre matched-pair analysis in a heterogeneous risk population.

BACKGROUND: Beside the transplantation of haematopoietic stem cells derived from bone marrow (BMT) and peripheral blood (PBSCT) in the absence of a well-matched donor, transplantation of cord blood (CBT) has been shown to be a valid alternative. To validate the efficacy of CBT in comparison to BMT and PBSCT we performed a single-centre based matched-pair analysis. PATIENTS AND METHODS: Between 1996 and 2003, 15 paediatric patients with non-malignant and malignant diseases of heterogenous risk underwent CBT. 198 paediatric patients undergoing BMT or PBSCT during the same time and at the same centre were available for selection as appropriate controls for matched-pair analysis. Matching criteria in descending hierarchy were disease, risk status, type of donor, age at HSCT, gender and year of transplantation. 47 % of CB grafts were < or = 4/6 HLA-matched whereas close to 90 % of grafts in the BMT and PBSCT cohorts were completely matched. RESULTS: Neutrophil engraftment was comparable in CB and BM recipients (p = 0.529) while engraftment following PBSCT occurs significantly earlier (p < 0.01). Median time to neutrophil recovery was 20 (range: 13-36), 19 (14-28) and 14 (9-24) days for the CBT, BMT and PBSCT cohort respectively. Of note contrary to the expectation, with regard to a reduced risk of Graft-versus-Host-Disease (GvHD) there was no clear advantage in the CBT cohort with a similar overall GvHD rate in all 3 groups. This observation can be attributed to the fact that in the CBT cohort the proportion of patients with an HLA-mismatched donor was higher than in the other cohorts. Rate of death of complications (DOC) was high in CB recipients (40 %), but not statistically different from BM (27 %) and PBSC recipients (13 %). In contrast to the CBT and BMT cohort with only 1 patient dead of disease (DOD), 4 PBSC recipients (31 %) died suffering from a relapse. 2-year event-free survival (EFS) in patients with malignant disease was 38.5 %, 69.2 % and 33.0 % for the CBT, BMT and PBSCT cohort respectively. 5-year overall survival (OS) was 53.3 % in the CBT, 66.4 % in the BMT and 50.9 % in the PBSCT cohort. There was no statistical difference between the cohorts transplanted with CB and BM or PBSC regarding EFS and OS (EFS: p = 0.24 and p = 0.72; OS: p = 0.53 and p = 0.64). CONCLUSIONS: Transplantation of < or = 4/6 HLA-matched CB grafts seems to be associated with a higher risk of GvHD, graft rejection and lethal opportunistic infection. With an overall survival of 53 % in our 15 patients this analysis documents that even in high risk patients, CB may be a valid alternate HSC source in children who lack a well-matched donor. This is especially true, if a > 4/6 HLA-matched CB with > 2.0 x 10 (7) total nucleated cells/kg bodyweight is available. Thus, parallel to the search for a BM or PBSC donor, searching for an adequate CB unit should be initiated.

Adolescent↗
PubMedDate not supplied

Similar survival following HLA-identical sibling transplantation for standard indication in children with haematologic malignancies: a single center comparison of mobilized peripheral blood stem cell with bone marrow transplantation.

BACKGROUND: Peripheral blood stem cell (PBSC) grafts are increasingly used for autologous and allogeneic haematopoietic stem cell transplantation (alloHSCT) with the aim to hasten neutrophil and platelet engraftment and thereby to reduce transplant-related complications due to infections, bleeding and graft failure. Based on the paucity of data on PBSC transplantation in children we performed a retrospective single-center analysis comparing the outcome of children receiving mobilized PBSC from human leukocyte antigen (HLA)-identical sibling donors to bone marrow (BM) transplant recipients. PATIENTS AND METHODS: Between 1996 and 2004, 16 children with haematologic malignancies and standard indication for alloHSCT underwent PBSC transplantation from HLA-identical sibling donors. The outcome of these children was compared to a historic control group of 19 bone marrow (BM) transplant recipients. Time to neutrophil engraftment, incidence of acute and chronic graft-versus-host disease (GvHD), relapse rate, transplant-related mortality, event-free and overall survival were analyzed. RESULTS: Neutrophil engraftment was achieved significantly faster after PBSC compared to BM transplantation with a median time to neutrophil engraftment of 11 (range: 8-21) and 19 (16-44) days for the PBSC and BM cohort, respectively (p < 0.001). Two of 19 (11 %) BM recipients did not achieve primary neutrophil engraftment and both patients died due to infectious complications. The rate of clinically significant acute GvHD > or = grade II was higher in the PBSC compared to the BM group (75 vs. 39 %; p = 0.045). Incidences of chronic GvHD (PBSC vs. BM: 60 vs. 44 %), death of disease (13 vs. 21 %) and death of complication (13 vs. 16 %) were comparable between both groups (p = ns). With a median follow up of 4.7 years (PBSC) and 10.2 years (BM) overall survival (PBSC vs. BM: 68.6 +/- 13.5 vs. 63.2 +/- 11.1 %; p = 0.65) and event-free survival (67.0 +/- 12.1 vs. 63.2 +/- 11.1 %; p = 0.80) is without demonstrable difference in both groups. CONCLUSIONS: Transplantation of PBSC compared to BM is associated with faster neutrophil engraftment and a higher rate of > or = grade II acute GvHD. As overall survival and event-free survival is similar when using PBSC and BM, PBSC is an alternative stem cell source for HLA-identical sibling transplantation. Further prospective analyses with higher number of patients stratified according to well established risk factors are required to define the precise role of both stem cell sources for children with haematologic malignancies.

Adolescent↗
PubMedDate not supplied

Immunotherapy in children: report from the Reisensburg-Symposium October 20-22, 2004 and recent advances.

Immunotherapy of childhood malignancies has a magic aura of promising an easy way to cure. It is not only the public, but also the medical community, which has caused this hope. Therefore, it was worthwhile to bring together a panel of experts working in the field of immunotherapy in order to discuss ongoing projects, and to show hopes and disappointments. The result was a fascinating symposium sponsored by The Kind Philipp Leukemia Foundation (Mönchengladbach, Germany). The symposium took place in the Reissensburg near Ulm (Germany) which gives the ideal location for such an event.

Age Factors↗
PubMedDate not supplied

[Immune stimulation with interleukin-2 after autologous stem cell transplantation in children and adolescents with solid tumors].

Children with solid tumors of poor prognosis have benefitted from autologous bone marrow transplantation as a treatment modality. Adjuvant interleukin-2 (IL2) therapy has previously been shown to improve prognosis in adults with some solid tumors. In this setting improved survival probability has been attributed to IL2-mediated augmentation of antineoplastic activity of the immune system. In this study 8 pediatric patients in complete remission after autologous stem cell transplantation were treated with recombinant IL2 administered in 3 cycles of 5 days continuous intravenous infusions and a two week rest in between. We demonstrated that IL2 therapy increased transplantation-related activation of the immune system both on cellular and humoral levels. Peripheral blood T and NK cell number increased by the factors 1.7 and 6.0 respectively. NK and T cell activation were further enhanced as indicated by elevated levels of soluble IL2 receptor. The production of tumor cytotoxic cytokines like alpha TNF and gamma INF was stimulated. The elevated aTNF and gamma INF cytokine synthesis seemed to be mainly related to the activation and proliferation of NK cells, as T cells obtained from patients after IL2 therapy showed a definite cytokine production deficiency after T cell specific stimulation.

Adolescent↗