Age, Thymopoiesis, and CD4+ T-Lymphocyte Regeneration after Intensive Chemotherapy
Crystal L. Mackall, M.D., Thomas A. Fleisher, M.D., Margaret R. Brown, B.S., Mary P. Andrich, M.D., Clara C. Chen, M.D., Irwin M. Feuerstein, M.D., Marc E. Horowitz, M.D., Ian T. Magrath, M.D., Aziza T. Shad, M.D., Seth M. Steinberg, Ph.D., Leonard H. Wexler, M.D., and Ronald E. Gress, M.D.
Background Inadequate reconstitution of CD4+ T lymphocytes isan important clinical problem complicating chemotherapy, humanimmunodeficiency virus infection, and bone marrow transplantation,but relatively little is known about how CD4+ T lymphocytesregenerate. There are two main possibilities: bone marrow–derivedprogenitors could reconstitute the lymphocyte population usinga thymus-dependent pathway, or thymus-independent pathways couldpredominate. Previous studies have suggested that the CD45RAglycoprotein on CD4+ T lymphocytes is a marker for progeny generatedby a thymus-dependent pathway.
Methods We studied 15 patients 1 to 24 years of age who hadundergone intensive chemotherapy for cancer. The absolute numbersof CD4+ T lymphocytes in peripheral blood and the expressionof CD45 isoforms (CD45RA and CD45RO) on these lymphocytes werestudied serially during lymphocyte regeneration after the completionof therapy. Radiographic imaging of the thymus was performedconcomitantly.
Results There was an inverse relation between the patients'ages and the CD4+ T-lymphocyte counts six months after therapywas completed (r = -0.92). The CD4+ recovery correlated quantitativelywith the appearance of CD45RA+CD4+ T lymphocytes in the blood(r = 0.64). There was a higher proportion of CD45RA+CD4+ T lymphocytesin patients with thymic enlargement after chemotherapy thanin patients without such enlargement (two-sided P = 0.015).
Conclusions Thymus-dependent regeneration of CD4+ T lymphocytesoccurs primarily in children, whereas even young adults havedeficiencies in this pathway. Our results suggest that rapidT-cell regeneration requires residual thymic function in patientsreceiving high-dose chemotherapy.
Depletion of CD4+ T lymphocytes is an important clinical problemin bone marrow transplantation1,2,3 and human immunodeficiencyvirus (HIV) infection.4 Yet the mechanisms by which CD4+ T lymphocytesregenerate are poorly understood. In 1961 Miller discoveredthe importance of the thymus in T-cell development in his studiesof neonatally thymectomized mice.5 Since then, extensive studieshave elucidated the role of the thymus in fetal T-cell development,6and there has been a general acceptance of the view that thethymus plays an ongoing part in T-cell generation. This viewunderlies the concept that HIV infection of the thymus contributesto the depletion of CD4+ T lymphocytes in the acquired immunodeficiencysyndrome (AIDS).7,8 Similarly, the idea that immunocompetenceafter bone marrow transplantation requires at least partialHLA matching between donor and recipient9 assumes that T-cellregeneration occurs by means of a thymic pathway.
The postnatal role of the thymus is unclear, however. The absenceof immunodeficiency in children and adults who have undergonethymectomy10,11 and the observation that the human thymus undergoesspontaneous involution at a relatively young age imply thatT-cell populations may be maintained by mechanisms largely independentof the thymus. It has thus been suggested that thymus-independentpathways may be important for the generation and maintenanceof T cells,12 and these pathways have been invoked to explainT-cell regeneration after bone marrow transplantation.13,14Clarifying the relative importance of the thymus-dependent andthymus-independent pathways may be an important step in devisingstrategies to improve the reconstitution of CD4+ T lymphocytesin disease states.
Because there is a substantial decrease in thymic size duringpuberty and thymic rebound has been reported in children afterchemotherapy,15 we have postulated that the contribution ofthe thymus to the regeneration of CD4+ T lymphocytes may varywith the patient's age. Previous work has shown that CD4+ Tlymphocytes exported from the thymus express the surface antigenCD45RA.16,17,18 We investigated CD45 isoform expression on CD4+T lymphocytes in patients 1 to 24 years of age during the regenerationof T cells after intensive cytotoxic chemotherapy. We foundage-related differences in CD4+ T-lymphocyte regeneration andevidence that children and young adults recovering from cytotoxicchemotherapy have different rates of thymopoiesis.
Methods
Patients and Protocols
Fifteen patients with histologic evidence of cancer were enrolledin studies conducted by the National Cancer Institute to treatbrain tumors (Pediatric Branch [PB] protocol 90-C-211), sarcoma(PB 86-C-169 and 93-C-125), and non-Hodgkin's lymphoma (PB 89-C-41and 93-C-207). In each study, the dose of cyclophosphamide wassubstantial, ranging from 1.2 to 4.5 g per square meter of body-surfacearea per cycle. The chemotherapy administered in protocols PB90-C-211, 86-C-169, and 89-C-41 has been described in detailelsewhere.19 Patients treated in protocols PB 93-C-125 and 93-C-207received sequential cycles of cyclophosphamide-containing drugsat doses of 2.4 and 1.2 g per square meter per cycle, respectively,administered at least every 21 days. All the protocols wereapproved by the institutional review board of the National CancerInstitute, and informed consent was obtained from all patientsor their parents before enrollment in the study.
No patient had detectable involvement of bone marrow with tumor.Three patients received radiation therapy: Patient 6 received6000 cGy to the right forearm, Patient 7 received 6600 cGy tothe buttocks and pelvis, and Patient 12 received 3000 cGy tothe cranium and spine. Patient 1 had HIV infection acquiredfrom his mother; before the development of lymphoma, his onlymanifestations of disease were chronic eczema and thrombocytopenia.All the patients were rendered free of detectable neoplasticdisease during chemotherapy. Twelve patients remained free ofdisease, whereas Patients 1, 9, and 14 relapsed 6, 18, and 8months after therapy, respectively.
Flow Cytometry
Specimens of peripheral blood were obtained during routine clinicvisits and were handled according to established clinical guidelines.The specimens were stained for flow cytometry with the whole-bloodlysis technique and analyzed with a FACScan (Becton Dickinson,San Jose, Calif.) with Lysis II software.19 The monoclonal antibodiesused included anti-CD3 (Leu-4) and anti-CD4 (Leu-3) (BectonDickinson), anti-CD45RO (UCHL1) (Dako, Carpinteria, Calif.),and anti-CD45RA (Alb11) (Gentrak, Plymouth Meeting, Pa.). Irrelevantantibodies of the IgG1, IgG2a, and IgG2b subclasses were usedto ascertain background staining. cd4+ T lymphocytes were definedas cells positive for both CD4 and CD3. cd4+ T lymphocytes withexclusive expression of CD45RA were designated as bearing high-molecular-weightisoforms of CD45, and those with exclusive expression of CD45ROwere designated as bearing low-molecular-weight isoforms. Tocalculate absolute numbers of each lymphocyte subgroup, thepercentage of cells staining positive was multiplied by theabsolute count of peripheral-blood lymphocytes as determinedby a Coulter counter (Coulter, Hialeah, Fla.) followed by adifferential leukocyte count in a blood sample obtained simultaneously.
Radiographic Imaging
As part of routine follow-up of their diseases, all the patientsexcept Patient 12 underwent radiographic imaging that includedimaging of the thymus. Patients 4, 6, 7, 9, 10, 11, and 15 underwentcomputed tomographic (CT) scanning of the chest, and Patients1, 2, 3, 4, 5, 8, 10, 13, 14, and 15 underwent scanning withgallium-67. The images of the thymus were analyzed seriallyfor most patients from the time of presentation until one yearafter the completion of therapy. Patients 1 and 8 were followedfor 6 months after therapy, and Patient 6 was followed for 10months. The mean (±SE) number of times the patients (exceptPatient 12) were studied for the occurrence of thymic reboundin the year after therapy was 4.3±0.5.
Radiographic evidence of thymic rebound was sought by the radiologistand the nuclear-medicine physicians. At the time of the analyses,these investigators were unaware of the degree of CD4+ T-lymphocyterecovery in individual patients. Thymic volumes were calculatedfrom CT images as described elsewhere,20 with thymic rebounddefined as at least a doubling of the thymic volume measuredat presentation. In the patients studied with gallium-67, increasedmediastinal uptake of gallium consistent with thymic reboundwas assessed as described elsewhere.15 Thymic rebound was definedas an uptake of gallium-67 in the anterior mediastinum not observedpreviously and having the characteristic size, shape, and locationof thymic activity. Patients who underwent imaging by both methodswere analyzed by each, with concordant results in all cases.
Because neither CT scanning nor gallium scanning can reliablydistinguish thymic rebound from recurrent tumor in the thymicregion,21 the radiographic studies were analyzed serially toascertain that the thymus had returned to the size observedat presentation. Such resolution of thymic enlargement in theabsence of clinical or radiographic evidence of recurrent tumorwas regarded as sufficient evidence that the increase in sizewas benign.
Statistical Analysis
Spearman correlation coefficients were calculated, and the Wilcoxonrank-sum test was used to compare measurements between patients.All P values are two-sided.
Results
Fifteen patients 1 to 24 years of age underwent intensive chemotherapyfor cancer with regimens containing oxazaphosphorines. Table 1contains data on each patient before, during, and after treatment.Although CD4+ T-lymphocyte counts were depressed in some patientsat the time of presentation, serial measurements showed furtherdepletion after chemotherapy, as reported elsewhere.19 The mean(±SE) CD4+ T-lymphocyte count after the completion ofchemotherapy in the 15 patients was 94.4±17.1 per cubicmillimeter. The extent of depletion was not related to the ageof the patients (r = 0.13).
Table 1. Depletion and Recovery of CD41 T Lymphocytes and Occurrence of Thymic Rebound in the Study Patients.
Age-Related Differences
CD4+ T lymphocytes were analyzed serially for at least six monthsafter the completion of chemotherapy. Younger patients had greaterrecovery of CD4+ T lymphocytes six months after chemotherapythan older patients, who had persistent severe depletion ofCD4+ T lymphocytes (Figure 1). There was an inverse correlationbetween the CD4+ T-lymphocyte count six months after therapyand the patient's age (r = -0.92). CD4+ T-lymphocyte countscan vary with age in normal people,18 but the severely depletedcounts in our older patients six months after therapy were wellbelow normal values for their age (as shown in the notes toTable 1). Analysis of the net increase in CD4+ T-lymphocytecounts from the completion of therapy until six months later(as derived from data in Table 1) showed a similar inverse relationto age (r = -0.90).
Figure 1. Relation between Age and Reconstitution of CD4+T Lymphocytes.
Absolute CD4+ T-lymphocyte counts were measured in the peripheral blood of patients approximately six months after the completion of chemotherapy. The correlation coefficient was calculated by the Spearman rank-correlation method.
Regeneration of CD45RA+CD4+ T Lymphocytes
CD45RA is expressed on recent emigrants from the thymus,16,17,18and work with T-cell regeneration in an animal model has shownthat CD4+ T lymphocytes expressing high-molecular-weight isoformsof CD45 (CD45RA) are regenerated from bone marrow progenitorsthrough a thymus-dependent pathway. By contrast, CD4+ T cellsderived from thymus-independent pathways express low-molecular-weightisoforms of CD45 (CD45RO) almost exclusively.22 In this seriesof patients, CD45RO was consistently expressed on essentiallyall CD4+ T lymphocytes during and immediately after intensivechemotherapy. The reason for this chemotherapy-associated changein phenotype is not known, but the phenomenon has been reportedpreviously.19 Because of it, newly generated CD45RA+CD4+ T lymphocytescould be readily detected.
To evaluate whether the age-related differences in the rateof CD4+ T-lymphocyte recovery after chemotherapy could be dueto differing rates of thymopoiesis, we prospectively evaluatedthe expression of CD45 isoforms on CD4+ T lymphocytes duringregeneration after chemotherapy. Data from two patients areshown in Figure 2A and Figure 2B. Panel A shows data from athree-year-old (Patient 2). During and immediately after chemotherapy,almost all CD4+ T lymphocytes expressed CD45RO (ratio of CD45RAto CD45RO [RA:RO ratio], 0.03). Six months after the completionof chemotherapy, increased numbers of CD45RA+CD4+ T lymphocytesappeared (RA:RO ratio, 1.4), at the same time as an increasein the absolute CD4+ T-lymphocyte count. In contrast, PanelB shows the persistence of CD45RO on essentially all CD4+ Tlymphocytes in a 23-year-old (Patient 12) for six months afterchemotherapy (RA:RO ratio, <0.01). Eight months after therapy,a few CD45RA+CD4+ T cells were seen (RA:RO ratio, 0.30), atthe same time as a slight increase in the CD4+ T-cell count.Fifteen months after chemotherapy, increased numbers of CD45RA+CD4+T lymphocytes were observed (RA:RO ratio, 0.96) in associationwith an increase in the number of CD4+ T lymphocytes. Figure 3shows the correlation between the RA:RO ratio and the netincrease in the CD4+ T-lymphocyte count six months after chemotherapy(r = 0.64).
Figure 2. Changes in the Number of CD4+ T Lymphocytes and in CD45 Isoforms during T-Cell Reconstitution.
Panel A shows changes in the number of CD4+ T lymphocytes and CD45 isoforms (CD45RA and CD45RO) during chemotherapy and 1, 2, 6, 8, and 10 months thereafter in a three-year-old patient (Patient 2). Panel B shows data for a 23-year-old patient (Patient 12). Three-color flow cytometry was used to gate on CD4+ T lymphocytes, and two-color immunofluorescence dot plots are shown. CD45RA (green dots) is the high-molecular-weight isoform and CD45RO (red dots) the low-molecular-weight isoform, both expressed by CD4+ T cells. Black dots represent CD4+ T cells with intermediate expression of both CD45RA and CD45RO. Values during chemotherapy were measured at the time of hematologic reconstitution after the cycle noted.
Figure 3. Relation between the RA:RO Ratio and the Recovery of CD4+ T Lymphocytes.
The net change in the CD4+ T-lymphocyte count six months after the completion of therapy was calculated by subtracting the nadir (Table 1) from the count six months after therapy. The RA:RO ratio was ascertained by flow cytometry six months after therapy. The data point for Patient 10 is not shown (the net change was zero), but this information was used in calculating the correlation coefficient.
The recovery of CD4+ T lymphocytes in one patient (Patient 3)did not follow a typical course with regard to the RA:RO ratioand the number of CD4+ T lymphocytes. The recovery of the CD4+T-lymphocyte count was brisk by three months after chemotherapy,but low numbers of CD45RA+CD4+ T lymphocytes persisted. Thepatient had a complicated course because of recurrent bowelobstruction that required bowel resection approximately sixmonths after chemotherapy. After his recovery from surgery,high RA:RO ratios appropriate for his age appeared, along witha further increase in the CD4+ T-lymphocyte count. These eventssuggest that lymphocyte activation related to clinical eventsmay confound changes in RA:RO ratios.
Radiographic Evidence of Thymic Rebound
Serial images of the thymus by CT scanning, radionuclide imaging,or both were obtained in 14 patients. Figure 4 shows CT scansof two patients at presentation and three months after chemotherapy.In an 11-year-old (Patient 4), the large anterior mediastinalmass after therapy aroused concern about recurrent lymphomaand prompted an open biopsy of the thymus. Histologic analysisrevealed normal thymic tissue. In contrast, CT scans of a 19-year-old(Patient 10) showed no increase in thymic size three monthsafter therapy.
Figure 4. CT Scanning of the Thymus before and after Chemotherapy.
The mediastinum is shown at presentation (left-hand panels) and three months after the completion of chemotherapy (right-hand panels). For an 11-year-old patient (Patient 4, upper panels), the calculated thymic volumes were 4.83 cm3 at presentation and 61.8 cm3 three months after chemotherapy. For a 19-year-old patient (Patient 10, lower panels), the volumes were 4.65 cm3 at presentation and 1.31 cm3 three months after chemotherapy.
Table 1 shows the maximal RA:RO ratio in each patient duringthe period after therapy when the images of the thymus wereobtained. The Wilcoxon rank-sum test revealed that the patientswith radiographic evidence of thymic rebound had significantlyhigher maximal RA:RO ratios than those without rebound duringthat period (P = 0.015). The patients with radiographic evidenceof thymic rebound were younger than those without such evidence(P = 0.017), and six months after the completion of therapythey had higher CD4+ T-lymphocyte counts (P = 0.011) and highernet increases in the counts (P = 0.007).
Discussion
Our evidence suggests that a thymopoietic pathway of CD4+ T-lymphocyteregeneration is important throughout childhood. However, thethymus appears to have a diminished capacity for regenerationof CD4+ T lymphocytes as it involutes with the approach of adulthood.Nevertheless, several patients who were at least 18 years ofage eventually had increased CD4+ T-lymphocyte counts that correlatedwith the appearance of sizable numbers of CD45RA+CD4+ T lymphocytes.Therefore, the capacity for regeneration of CD4+ T lymphocytesafter chemotherapy appears to diminish with age, but it is unclearwhether there is an age after which the thymus loses its regenerativecapacity completely. Further studies in older adults are neededto address this issue. Our finding suggests, however, that anytherapy or disease state that depletes CD4+ T cells may havea more profound effect in older patients than in children.
With regard to the chemotherapy-induced depletion of CD4+ Tlymphocytes, four of the eight patients in this study who wereat least 18 years old at the time of presentation had opportunisticinfectious complications19 during their prolonged periods ofCD4+ T-cell lymphopenia. In contrast, such complications developedin only one of the seven patients in this study who were under18 years of age. The number of patients we evaluated was toosmall to permit us to ascertain the true incidence of opportunisticcomplications in relation to age in patients undergoing chemotherapy,but our findings suggest that in the setting of intensive chemotherapy,thymic production of CD4+ T lymphocytes may help protect patientsfrom clinically important immunodeficiency.
The information presented here may help to further our understandingof the causes of inadequate recovery of CD4+ T lymphocytes inHIV infection and other clinical settings. It is known thatHIV can infect thymocytes and thymic epithelium,7,8 and someevidence suggests that thymus-dependent pathways may be deficienteven in young patients with HIV infection.23 However, studiesof the regeneration of CD45RA+CD4+ T lymphocytes and thymicimaging in the HIV-infected child in this series suggest thata thymic-dependent pathway of CD4+ T-lymphocyte reconstitutiondid function despite HIV infection. Furthermore, there is preliminaryevidence that in children receiving antiviral dideoxynucleotidesto treat HIV infection there is a more sustained increase inthe CD4+ T-lymphocyte count than in adults similarly treated.24These data suggest that thymopoiesis may indeed be importantfor the regeneration of CD4+ T lymphocytes in the setting ofHIV infection.
Our work has implications for new therapies being undertakenin HIV infection and bone marrow transplantation. For example,for gene therapy using genes for resistance to HIV to succeed,25,26,27it is critical that the targeted cell be a progenitor of long-livedCD4+ T lymphocytes. Placing these genes into prethymic stemcells would be logical in patients with intact thymopoieticpathways. If, however, the thymic pathway has been compromisedby either advancing age or progressive disease, targeting prethymicbone marrow progenitors may not result in sufficient progenyto yield a beneficial outcome. Similarly, the use of highlypurified populations of bone marrow stem cells to reconstitutemarrow function in transplant recipients28 may result in varyingdegrees of immune reconstitution, depending on the age of thepatient. The studies described here may provide a means of evaluatingand interpreting the results of such therapeutic strategiesand of studying T-cell regeneration in a variety of clinicalsettings.
We are indebted to the nurses of the Star Team, 13th floor OutpatientClinic, Pediatric Branch, National Cancer Institute, for theirdiligence in obtaining specimens for analysis; to the RainbowTeam of the Pediatric Branch and the staff and nurses of theDivisions of Pediatric Hematology and Oncology of the HersheyMedical Center, Hershey, Pa., and Children's National MedicalCenter, Washington, D.C., for contributing samples from patients;and to Dr. Richard Hodes and Dr. Gene Shearer for their carefulreview of the manuscript.
Source Information
From the Experimental Immunology Branch, Division of Cancer Biology, Diagnosis, and Centers (C.L.M., R.E.G.), the Medicine (R.E.G.) and Pediatric (M.E.H., I.T.M., A.T.S., L.H.W.) Branches, Division of Cancer Treatment, and the Biostatistics and Data Management Section (S.M.S.), National Cancer Institute; the Departments of Nuclear Medicine (M.P.A., C.C.C.), Clinical Pathology (T.A.F., M.R.B.), and Radiology (I.M.F.), Clinical Center, National Institutes of Health; and the Henry M. Jackson Foundation for the Advancement of Military Medicine, Uniformed Services University for the Health Sciences (I.M.F.) — all in Bethesda, Md.
Address reprint requests to Dr. Mackall at Bldg. 10, Rm. 4B14, National Institutes of Health, Bethesda, MD 20892.
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Regeneration of T Cells after Chemotherapy
Cunnane G., O'Farrelly C., Michie C. A., McLean A. R., Moreland L. W., Bucy R. P., Koopman W. J., Mackall C. L., Steinberg S. M., Gress R. E.
Extract |
Full Text
N Engl J Med 1995;
332:1650-1652, Jun 15, 1995.
Correspondence
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Sutherland, J. S., Spyroglou, L., Muirhead, J. L., Heng, T. S., Prieto-Hinojosa, A., Prince, H. M., Chidgey, A. P., Schwarer, A. P., Boyd, R. L.
(2008). Enhanced Immune System Regeneration in Humans Following Allogeneic or Autologous Hemopoietic Stem Cell Transplantation by Temporary Sex Steroid Blockade. Clin. Cancer Res.
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Lilleri, D., Fornara, C., Chiesa, A., Caldera, D., Alessandrino, E. P., Gerna, G.
(2008). Human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in adult allogeneic hematopoietic stem cell transplant recipients and immune control of viral infection. haematol
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(2007). Multiple prethymic defects underlie age-related loss of T progenitor competence. Blood
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Kochenderfer, J. N., Simpson, J. L., Chien, C. D., Gress, R. E.
(2007). Vaccination regimens incorporating CpG-containing oligodeoxynucleotides and IL-2 generate antigen-specific antitumor immunity from T-cell populations undergoing homeostatic peripheral expansion after BMT. Blood
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Seggewiss, R., Lore, K., Guenaga, F. J., Pittaluga, S., Mattapallil, J., Chow, C. K., Koup, R. A., Camphausen, K., Nason, M. C., Meier-Schellersheim, M., Donahue, R. E., Blazar, B. R., Dunbar, C. E., Douek, D. C.
(2007). Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques.. Blood
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Goldberg, G. L., Alpdogan, O., Muriglan, S. J., Hammett, M. V., Milton, M. K., Eng, J. M., Hubbard, V. M., Kochman, A., Willis, L. M., Greenberg, A. S., Tjoe, K. H., Sutherland, J. S., Chidgey, A., van den Brink, M. R. M., Boyd, R. L.
(2007). Enhanced Immune Reconstitution by Sex Steroid Ablation following Allogeneic Hemopoietic Stem Cell Transplantation. J. Immunol.
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Kim, Y. H., Duvic, M., Obitz, E., Gniadecki, R., Iversen, L., Osterborg, A., Whittaker, S., Illidge, T. M., Schwarz, T., Kaufmann, R., Cooper, K., Knudsen, K. M., Lisby, S., Baadsgaard, O., Knox, S. J.
(2007). Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma. Blood
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Prasad, A. S.
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Rossi, S. W., Jeker, L. T., Ueno, T., Kuse, S., Keller, M. P., Zuklys, S., Gudkov, A. V., Takahama, Y., Krenger, W., Blazar, B. R., Hollander, G. A.
(2007). Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood
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Min, D., Panoskaltsis-Mortari, A., Kuro-o, M., Hollander, G. A., Blazar, B. R., Weinberg, K. I.
(2007). Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood
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Maillard, I., Schwarz, B. A., Sambandam, A., Fang, T., Shestova, O., Xu, L., Bhandoola, A., Pear, W. S.
(2006). Notch-dependent T-lineage commitment occurs at extrathymic sites following bone marrow transplantation. Blood
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de Kleer, I., Vastert, B., Klein, M., Teklenburg, G., Arkesteijn, G., Yung, G. P., Albani, S., Kuis, W., Wulffraat, N., Prakken, B.
(2006). Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network. Blood
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Ogle, B. M., West, L. J., Driscoll, D. J., Strome, S. E., Razonable, R. R., Paya, C. V., Cascalho, M., Platt, J. L.
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Chalandon, Y., Degermann, S., Villard, J., Arlettaz, L., Kaiser, L., Vischer, S., Walter, S., Heemskerk, M. H. M., van Lier, R. A. W., Helg, C., Chapuis, B., Roosnek, E.
(2006). Pretransplantation CMV-specific T cells protect recipients of T-cell-depleted grafts against CMV-related complications. Blood
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Curtis, J. L.
(2005). Cell-mediated Adaptive Immune Defense of the Lungs. Proc Am Thorac Soc
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Heng, T. S. P., Goldberg, G. L., Gray, D. H. D., Sutherland, J. S., Chidgey, A. P., Boyd, R. L.
(2005). Effects of Castration on Thymocyte Development in Two Different Models of Thymic Involution. J. Immunol.
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Haining, W. N., Neuberg, D. S., Keczkemethy, H. L., Evans, J. W., Rivoli, S., Gelman, R., Rosenblatt, H. M., Shearer, W. T., Guenaga, J., Douek, D. C., Silverman, L. B., Sallan, S. E., Guinan, E. C., Nadler, L. M.
(2005). Antigen-specific T-cell memory is preserved in children treated for acute lymphoblastic leukemia. Blood
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Caraglia, M., Montella, L., Addeo, R., Costanzo, R., Faiola, V., Del Prete, S., Baldi, F., Baldi, A., Abbruzzese, A., Alloisio, M.
(2005). Conditions Suggesting Lymphoma: CASE 2. Mediastinal Liposarcoma in a Patient With Previous Testicular Cancer. JCO
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Naylor, K., Li, G., Vallejo, A. N., Lee, W.-W., Koetz, K., Bryl, E., Witkowski, J., Fulbright, J., Weyand, C. M., Goronzy, J. J.
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Muraro, P. A., Douek, D. C., Packer, A., Chung, K., Guenaga, F. J., Cassiani-Ingoni, R., Campbell, C., Memon, S., Nagle, J. W., Hakim, F. T., Gress, R. E., McFarland, H. F., Burt, R. K., Martin, R.
(2005). Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. JEM
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(2004). Establishment of the CD4+ T-cell pool in healthy children and untreated children infected with HIV-1. Blood
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Flieder, D. B., Vora, S. K., Sanders, A., Gelbman, B.
(2004). Benign Thymic Hyperplasia As a Cause of Anterior Mediastinal Mass After Chemotherapy. Chest Meeting
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Winsor-Hines, D., Merrill, C., O'Mahony, M., Rao, P. E., Cobbold, S. P., Waldmann, H., Ringler, D. J., Ponath, P. D.
(2004). Induction of Immunological Tolerance/Hyporesponsiveness in Baboons with a Nondepleting CD4 Antibody. J. Immunol.
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McCloskey, T. W., Haridas, V., Pontrelli, L., Pahwa, S.
(2004). Response to Superantigen Stimulation in Peripheral Blood Mononuclear Cells from Children Perinatally Infected with Human Immunodeficiency Virus and Receiving Highly Active Antiretroviral Therapy. CVI
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Chu, Y.-W., Memon, S. A., Sharrow, S. O., Hakim, F. T., Eckhaus, M., Lucas, P. J., Gress, R. E.
(2004). Exogenous IL-7 increases recent thymic emigrants in peripheral lymphoid tissue without enhanced thymic function. Blood
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Feeney, M. E., Draenert, R., Roosevelt, K. A., Pelton, S. I., McIntosh, K., Burchett, S. K., Mao, C., Walker, B. D., Goulder, P. J. R.
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Poulin, J.-F., Sylvestre, M., Champagne, P., Dion, M.-L., Kettaf, N., Dumont, A., Lainesse, M., Fontaine, P., Roy, D.-C., Perreault, C., Sekaly, R.-P., Cheynier, R.
(2003). Evidence for adequate thymic function but impaired naive T-cell survival following allogeneic hematopoietic stem cell transplantation in the absence of chronic graft-versus-host disease. Blood
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Cuadrado, S. P., Moreno Koch, M. d. C., Perez, C. F., Castejon Castan, L. M., Villalobos, C. P., Gonzalez Mateos, M. J., Olmos, C. L.
(2003). Immunomodulation in Established Murine Tumors: Response and Survival Rate Enhancement by Blood Leukocyte-Augmenting Substance 236 (Cl-), a Novel Synthetic Compound. Clin. Cancer Res.
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Schonland, S. O., Zimmer, J. K., Lopez-Benitez, C. M., Widmann, T., Ramin, K. D., Goronzy, J. J., Weyand, C. M.
(2003). Homeostatic control of T-cell generation in neonates. Blood
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de la Rosa, R., Leal, M.
(2003). Thymic involvement in recovery of immunity among HIV-infected adults on highly active antiretroviral therapy. J Antimicrob Chemother
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Little, R. F., Pittaluga, S., Grant, N., Steinberg, S. M., Kavlick, M. F., Mitsuya, H., Franchini, G., Gutierrez, M., Raffeld, M., Jaffe, E. S., Shearer, G., Yarchoan, R., Wilson, W. H.
(2003). Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood
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Wedderburn, L R, Abinun, M, Palmer, P, Foster, H E
(2003). Autologous haematopoietic stem cell transplantation in juvenile idiopathic arthritis. Arch. Dis. Child.
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Malphettes, M., Carcelain, G., Saint-Mezard, P., Leblond, V., Altes, H. K., Marolleau, J.-P., Debre, P., Brouet, J.-C., Fermand, J.-P., Autran, B.
(2003). Evidence for naive T-cell repopulation despite thymus irradiation after autologous transplantation in adults with multiple myeloma: role of ex vivo CD34+ selection and age. Blood
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Roelofs, H., de Pauw, E. S. D., Zwinderman, A. H., Opdam, S. M., Willemze, R., Tanke, H. J., Fibbe, W. E.
(2003). Homeostasis of telomere length rather than telomere shortening after allogeneic peripheral blood stem cell transplantation. Blood
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Ponchel, F., Morgan, A. W., Bingham, S. J., Quinn, M., Buch, M., Verburg, R. J., Henwood, J., Douglas, S. H., Masurel, A., Conaghan, P., Gesinde, M., Taylor, J., Markham, A. F., Emery, P., van Laar, J. M., Isaacs, J. D.
(2002). Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis. Blood
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Ribeiro, R. M., Mohri, H., Ho, D. D., Perelson, A. S.
(2002). In vivo dynamics of T cell activation, proliferation, and death in HIV-1 infection: Why are CD4+ but not CD8+ T cells depleted?. Proc. Natl. Acad. Sci. USA
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Buseyne, F., Scott-Algara, D., Porrot, F., Corre, B., Bellal, N., Burgard, M., Rouzioux, C., Blanche, S., Riviere, Y.
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Sinha, M. L., Fry, T. J., Fowler, D. H., Miller, G., Mackall, C. L.
(2002). Interleukin 7 worsens graft-versus-host disease. Blood
100: 2642-2649
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Lewin, S. R., Heller, G., Zhang, L., Rodrigues, E., Skulsky, E., van den Brink, M. R. M., Small, T. N., Kernan, N. A., O'Reilly, R. J., Ho, D. D., Young, J. W.
(2002). Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantations. Blood
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Min, D., Taylor, P. A., Panoskaltsis-Mortari, A., Chung, B., Danilenko, D. M., Farrell, C., Lacey, D. L., Blazar, B. R., Weinberg, K. I.
(2002). Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood
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Franco, J. M., Rubio, A., Martinez-Moya, M., Leal, M., Merchante, E., Sanchez-Quijano, A., Lissen, E.
(2002). T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy. Blood
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Fry, T. J., Mackall, C. L.
(2002). Interleukin-7: from bench to clinic. Blood
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Heitger, A., Winklehner, P., Obexer, P., Eder, J., Zelle-Rieser, C., Kropshofer, G., Thurnher, M., Holter, W.
(2002). Defective T-helper cell function after T-cell-depleting therapy affecting naive and memory populations. Blood
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Hazenberg, M. D., Otto, S. A., de Pauw, E. S., Roelofs, H., Fibbe, W. E., Hamann, D., Miedema, F.
(2002). T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events. Blood
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Okamoto, Y., Douek, D. C., McFarland, R. D., Koup, R. A.
(2002). Effects of exogenous interleukin-7 on human thymus function. Blood
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Talvensaari, K., Clave, E., Douay, C., Rabian, C., Garderet, L., Busson, M., Garnier, F., Douek, D., Gluckman, E., Charron, D., Toubert, A.
(2002). A broad T-cell repertoire diversity and an efficient thymic function indicate a favorable long-term immune reconstitution after cord blood stem cell transplantation. Blood
99: 1458-1464
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French, R. A., Broussard, S. R., Meier, W. A., Minshall, C., Arkins, S., Zachary, J. F., Dantzer, R., Kelley, K. W.
(2002). Age-Associated Loss of Bone Marrow Hematopoietic Cells Is Reversed by GH and Accompanies Thymic Reconstitution. Endocrinology
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de Gast, G. C., Vyth-Dreese, F. A., Nooijen, W., van den Bogaard, C. J.C., Sein, J., Holtkamp, M. M.J., Linthorst, G. A.M., Baars, J. W., Schornagel, J. H., Rodenhuis, S.
(2002). Reinfusion of Autologous Lymphocytes With Granulocyte-Macrophage Colony-Stimulating Factor Induces Rapid Recovery of CD4+ and CD8+ T Cells After High-Dose Chemotherapy for Metastatic Breast Cancer. JCO
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Ho, V. T., Soiffer, R. J.
(2001). The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood
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Blazevic, V., Jankelevich, S., Steinberg, S. M., Jacobsen, F., Yarchoan, R., Shearer, G. M.
(2001). Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus Type 1-Infected Children: Analysis of Cellular Immune Responses. CVI
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Chung, B., Barbara-Burnham, L., Barsky, L., Weinberg, K.
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Waller, E. K., Rosenthal, H., Jones, T. W., Peel, J., Lonial, S., Langston, A., Redei, I., Jurickova, I., Boyer, M. W.
(2001). Larger numbers of CD4bright dendritic cells in donor bone marrow are associated with increased relapse after allogeneic bone marrow transplantation. Blood
97: 2948-2956
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Fry, T. J., Connick, E., Falloon, J., Lederman, M. M., Liewehr, D. J., Spritzler, J., Steinberg, S. M., Wood, L. V., Yarchoan, R., Zuckerman, J., Landay, A., Mackall, C. L.
(2001). A potential role for interleukin-7 in T-cell homeostasis. Blood
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Volpi, I., Perruccio, K., Tosti, A., Capanni, M., Ruggeri, L., Posati, S., Aversa, F., Tabilio, A., Romani, L., Martelli, M. F., Velardi, A.
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Fry, T. J., Christensen, B. L., Komschlies, K. L., Gress, R. E., Mackall, C. L.
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Kamradt, T., Mitchison, N. A.
(2001). Tolerance and Autoimmunity. NEJM
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Weinberg, K., Blazar, B. R., Wagner, J. E., Agura, E., Hill, B. J., Smogorzewska, M., Koup, R. A., Betts, M. R., Collins, R. H., Douek, D. C.
(2001). Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood
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Sempowski, G. D., Thomasch, J. R., Gooding, M. E., Hale, L. P., Edwards, L. J., Ciafaloni, E., Sanders, D. B., Massey, J. M., Douek, D. C., Koup, R. A., Haynes, B. F.
(2001). Effect of Thymectomy on Human Peripheral Blood T Cell Pools in Myasthenia Gravis. J. Immunol.
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Andrew, D., Aspinall, R.
(2001). IL-7 and Not Stem Cell Factor Reverses Both the Increase in Apoptosis and the Decline in Thymopoiesis Seen in Aged Mice. J. Immunol.
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Tsark, E. C., Dao, M. A., Wang, X., Weinberg, K., Nolta, J. A.
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Blazar, B. R., Lees, C. J., Martin, P. J., Noelle, R. J., Kwon, B., Murphy, W., Taylor, P. A.
(2000). Host T Cells Resist Graft-Versus-Host Disease Mediated by Donor Leukocyte Infusions. J. Immunol.
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Anderson, L. D. Jr., Mori, S., Mann, S., Savary, C. A., Mullen, C. A.
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Roux, E., Dumont-Girard, F., Starobinski, M., Siegrist, C.-A., Helg, C., Chapuis, B., Roosnek, E.
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Ragg, S., Xu-Welliver, M., Bailey, J., D’Souza, M., Cooper, R., Chandra, S., Seshadri, R., Pegg, A. E., Williams, D. A.
(2000). Direct Reversal of DNA Damage by Mutant Methyltransferase Protein Protects Mice against Dose-intensified Chemotherapy and Leads to in Vivo Selection of Hematopoietic Stem Cells. Cancer Res.
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Mackall, C. L., Stein, D., Fleisher, T. A., Brown, M. R., Hakim, F. T., Bare, C. V., Leitman, S. F., Read, E. J., Carter, C. S., Wexler, L. H., Gress, R. E.
(2000). Prolonged CD4 depletion after sequential autologous peripheral blood progenitor cell infusions in children and young adults. Blood
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Clark, D. R., Repping, S., Pakker, N. G., Prins, J. M., Notermans, D. W., Wit, F. W. N. M., Reiss, P., Danner, S. A., Coutinho, R. A., Lange, J. M. A., Miedema, F.
(2000). T-cell progenitor function during progressive human immunodeficiency virus-1 infection and after antiretroviral therapy. Blood
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Lin, M.-T., Tseng, L.-H., Frangoul, H., Gooley, T., Pei, J., Barsoukov, A., Akatsuka, Y., Hansen, J. A.
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Verfuerth, S., Peggs, K., Vyas, P., Barnett, L., O'Reilly, R. J., Mackinnon, S.
(2000). Longitudinal monitoring of immune reconstitution by CDR3 size spectratyping after T-cell-depleted allogeneic bone marrow transplant and the effect of donor lymphocyte infusions on T-cell repertoire. Blood
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Fagnoni, F. F., Vescovini, R., Passeri, G., Bologna, G., Pedrazzoni, M., Lavagetto, G., Casti, A., Franceschi, C., Passeri, M., Sansoni, P.
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Storek, J., Dawson, M. A., Maloney, D. G.
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