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TRANSPLANTATION
From the Division of Immunology and Allergology,
Division of Oncology, and Division of Hematology, Department of
Internal Medicine; and Center for Vaccinology and Neonatal Immunology,
Department of Pathology and Pediatrics, University Hospital, Geneva,
Switzerland.
To evaluate the importance of the thymus for the reconstitution of
immunity in recipients of a T-cell-depleted bone marrow, we measured
the appearance of CD4+CD45RA+RO Stem cell transplantation (SCT) is an established
treatment for various hematological disorders.1-6
Unfortunately, the transplant procedure causes a severe immune
deficiency, resulting in numerous, often life-threatening
infections.7-10 Because during the first weeks after
transplant, every hematological lineage is affected, initially all arms
of the immune system are deficient. Late complications are usually due
to malfunctioning of the T-cell compartment, and infectious morbidity
correlates with low CD4+ T-cell counts.11
Although the nature of infections in long-term survivors of SCT pointed
clearly at a T-cell deficiency,7,11-15 the reason T-cell
immunity remained impaired despite a rapid recovery of normal numbers
of T lymphocytes has been uncovered only recently. It has been shown
that once the T-cell compartment has been eradicated, it is
reconstituted through 2 different pathways.16-20 One is
thymus dependent and produces T cells with a very diverse
repertoire.20 Initially however, the T-cell compartment is
reconstituted through expansion of mature T cells. Because these cells
are the progeny of only a limited number of precursors, their T-cell
receptor (TCR) repertoire is of limited
diversity.21
While unbalanced T-cell repertoires have been observed after several
treatments affecting lymphocyte viability, the phenomenon is most
evident in patients transplanted with a T-cell-depleted graft.21-23 Here, the number of mature T cells
cotransfused with the graft is so low that some TCRBV (beta variable
region) families may consist of only a single
clone.20 In addition, when T-cell depletion is performed
only on the graft, the number of donor T cells transfused is in the
same order of magnitude as the number of recipient T cells that have
survived the conditioning. Because the T-cell depletion also reduces
the antihost activity of the graft, recipient T cells may expand to
form a significant part of the peripheral T-cell
pool.24,25 Because of the combination of these phenomena,
it is very instructive to study recipients of T-cell-depleted
allografts as a model for the rules of the reconstitution of T-cell
immunity after transplant. Another consequence of the very low
number of T cells at the time of transplant is that after the expansion
phase, the expanded cells completely dominate the cells that have
remained quiescent. The ensuing homogeneous expression of memory
markers significantly facilitates the study of the reconstitution of
the T-cell pool through the thymic pathway, since even a low thymic
activity will be spotted by the reappearance of
CD4+CD45RA+RO Blood samples
Fluorescence-activated cell analysis/sorting
Proliferation assay Cells (1 × 105/flat-bottom well) were cultured in 200 µL of RPMI 1640 medium, 100 IU/mL penicillin, 100 µg/mL streptomycin, 1 mmol/L sodium pyruvate, nonessential amino acids, and 2 mmol/L L-Glutamin (Life Technologies), supplemented with 5% human AB serum and 10 5 mol/L
 -mercaptoethanol (Sigma, St. Louis, MO). We added 1/4000 tetanus
toxoid (TT) (Institut Mérieux, Lyons, France) as a stimulus. After 6 days of culture, the proliferative responses were measured by
the amount of 3H-thymidine (5 µCi/well, 25 mCi/mmol)
(Amersham-Pharmacia, Uppsala, Sweden) incorporated after an additional
8-hour pulse. Responses are expressed as the stimulation index (cpm
response/cpm background) normalized to that of a normal
control. Cells lines were established after 10 days of
culture. Cloning of antigen-specific cells was done as previously
described.26
Analysis of the recipient/donor origin of the cells The recipient/donor origin of cells was determined on phytohemagglutinin-stimulated (Murex Biotech Ltd, Dartford, UK) clones derived from the sorted TCRBV2 cells from patient number 9 at 6 and 24 months post-SCT as described previously.24 Briefly, high molecular weight DNA was prepared from nuclei solubilized in Triton-X100 (Sigma) and incubated with proteinase K (Promega Corporation, Madison, WI) followed by polymerase chain reaction (PCR) with the minisatellite 33.1 primers. The amplification mixtures were separated on 1% agarose gels, and the origin of the clones was determined by comparison with the recipient (pre-SCT) and donor-specific profiles.Spectratype analysis All procedures as well as the sequences of oligonucleotides corresponding to the 21 variable segments of the TCR beta chain used in this study have been published previously.20 In brief, total RNA and complementary DNA were prepared from 2000 and 8000 CD3+ cells with the use of RNeasy kits from Qiagen (Hilden, Germany). PCR was performed with 6-FAM-, HEX-, and TET-5'-labeled primers (Amplimmun, Madulain, Switzerland), which allows amplification and analysis of multiple TCRBV segments in the same reaction. Data analysis was performed with the Genescan analysis software (Perkin Elmer, Rotkreuz, Switzerland).
Reconstitution of the T-cell compartment by CD4+ T cells in patients transplanted with an in vitro T-cell-depleted bone marrow Table 1 shows the age, type of disease, conditioning, and post-transplant immune suppression regimen for the patients studied. All patients (ages 17 through 52, patient numbers in order of age) were transplanted for leukemia in first remission with a Campath-1M T-cell-depleted marrow27 from an HLA-identical sibling. Engraftment (more than 0.5 × 109/L polymorphonuclear leukocytes) occurred between 17 and 35 days after transplant, and all patients remained in complete remission during the time of the study. Two patients (patient number 7, patient number 8) showed mild signs of graft-versus-host disease (GVHD); patient number 7 suffered from chronic GVHD, for which this patient received immune suppression during 19 months posttransplant. Figure 1 shows that with the exception of patient number 7, CD4+ T cells reconstituted rapidly, and no correlation between the number of CD4+ T cells and the age of the patient was observed. The reconstitution occurred in 2 phases. During the first 6 months after transplant, CD4+ T cells were generated exclusively through expansion of mature T cells, which was evident for 2 different reasons. First, no cells with a CD45RA+RO naive
phenotype of thymic emigrants were detected, confirming that after
intense conditioning, the thymus activity recovers only with a
considerable lagtime.18 Second, a significant percentage (28 ± 17; range, 5-60) of the T cells were of recipient
origin.20,22,25 Because the increase in cell numbers took
place in the absence of a recipient bone marrow24 and
therefore, in the absence of T-cell precursors, it is evident that this
increase must have occurred through peripheral expansion of the few
cells that had survived the conditioning. At approximately 6 months
after transplant, the first CD4+ T cells with a
CD45RA+RO naive phenotype appeared. These
cells were very likely thymic emigrants because they were of 100%
donor origin.28 As a consequence, the ratio between
recipient and donor T cells (11 ± 10; range, 5-40 at 2 years after
SCT) diminished significantly.22 Furthermore, as reported
by others,18,29 naive CD4+ cells seemed to
recover faster in younger patients, 2 of whom already had normal
numbers (200/µL or greater) of naive CD4+ T cells in
their circulation at 1 year after transplant. In contrast, the other
patients reconstituted much more slowly. These differences could be
very significant, with 3 patients being almost void of naive
CD4+ T cells at 1 year after transplant.
Reconstitution of the TCR repertoire by thymic emigrants Reconstitution of the T-cell compartment by expansion restores T-cell numbers without reconstituting the diversity of the T-cell repertoire.21 This is true not only for patients transplanted with T-cell-depleted grafts, who receive low numbers of T cells at the time of transplant, but also for recipients of unmanipulated grafts.22 Consequently, reactivity against numerous antigens may be lost. TCR diversity can be assessed by spectratyping, a method of measuring the size heterogeneity of the TCR hypervariable CDR3 region. Spectratypes from normal repertoires are complex and show a Gaussian distribution of 8 to 10 bands, representing the different lengths of the respective TCR V-D-J regions. In contrast, spectratypes from individuals with a limited TCR repertoire show gaps owing to the absence of clones with V-D-J regions of the corresponding length. We have previously shown that these gaps in the repertoire disappear during the second year after SCT owing to the appearance of T cells with a CD45RA+RO naive phenotype with a
normal, diverse repertoire.20 If these cells are produced
by the thymus, they should be exclusively of donor origin because no
recipient stem cells exist anymore to produce the necessary precursors.
Figure 2 shows a detailed analysis of the
diversification of the BV2-family in patient number 9. In the upper
panel, we performed a spectratype analysis on 2.103
TCRBV2-sorted T cells from blood samples at 190 and 730 days after
transplant. The results show that the repertoire at day 190, which was
dominated by a band at 142 bp, had diversified at day 730 to the extent
that the spectratype had become indistinguishable from that of a normal
donor.20 The repertoire diversification of the T-cell pool
that still contained significant numbers (more than 70%) of recipient
T cells25 was due solely to the appearance of donor T cells
with a random repertoire. This is shown in the middle and lower panel,
where we separated the BV2-expressing T cells of donor and recipient
origin by in vitro cloning of T cells under limiting dilution
conditions. Clearly, the repertoire of the recipient T cells did not
change because the spectratype of day 190 (15 clones pooled) was almost
identical to that of day 730 (33 clones pooled). In contrast, the
day-730 spectratype of the donor T cells (33 clones pooled) was almost
as complete as that of the 2.103 TCRBV2 T cells sorted
originally. Thus, the repertoire diversification between day 190 and
day 730 was due entirely to donor T cells that were absent during the
first 6 months after transplant. Holes in the repertoire can be
repaired only through production of new T cells by the thymus.
Therefore, the reconstitution of TCR diversity must initially correlate
with the extent of the thymic rebound. Although this will be true for
CD4+ as well as CD8+ T cells, thymic activity
is most easily monitored by the production of
CD4+CD45RA+RO T
cells18 because the phenotypes of naive CD8+ T
cells are more complex.30 Quantification of the TCR
diversity is possible by determining the percentage of complete
spectratypes in samples of low numbers of T cells.20 We
have shown that in samples of normal individuals containing as few as
8.103 T cells, the spectratypes of approximately 80% of
the TCRBV families are complete. This percentage is significantly lower
in patients with restricted T-cell repertoires.20 Figure
3A shows the changes in TCR diversity by
comparison of the number of complete TCRBV spectratypes generated by a
sample of 8.103 T cells taken at different time points
after transplant. It shows that after 6 months, the TCR repertoire of
all patients was still significantly below normal. At 1 year, only the
youngest patients (black symbols) showed repertoire complexities
comparable to that of normal individuals. Other patients reconstituted
much more slowly, and even at 2 years after transplant, 3 of 10 patients still had very limited repertoires. This was clearly due to
the low rate at which their T-cell compartment was reconstituted by naive T cells (Figure 3B). With the exception of the samples in which the spectratypes reflected merely the expanded memory
T-cell pool (fewer than 20 to 30/µL naive cells), TCR
diversity correlated well with the number of
CD4+CD45RA+RO T cells in the
blood. Because these naive T cells are exclusively of donor
origin28 and do not emerge when the patient is
thymectomized,31 it is evident that the restoration of
T-cell repertoire depends on stem cells producing pre-T cells as well
as on a functioning thymus.
A thymic rebound is essential to respond to vaccinations After SCT, T-cell memory is lost and patients have to be revaccinated.8,10,32,33 Because patients respond poorly during the first year after transplant,32 vaccinations are usually postponed to the second or third year. An obvious explanation for this late recovery is that the lack of responsiveness is the effect of the holes in the T-cell repertoire. If so, unresponsiveness will last until the thymus has produced new antigen-specific T cells. Therefore, although the responding cell itself will express memory markers, the extent of the response will correlate with the size of the naive pool, which reflects the thymic rebound. Figure 4 shows that for the 9 patients who had lost their in vitro anti-TT response completely (not shown), this was indeed the case. Of the 3 patients immunized at 1 year after transplant, only patient number 10, a 53-year-old patient whose thymic rebound was only slightly inferior to that of the young patients (Figure 1) responded. In contrast, for the 2 patients in whom the thymic rebound was less evident, even 3 boosts with TT remained ineffective. The same correlation between the response and the extent of thymic rebound existed for the patients immunized much later. Patient number 4 and patient number 7, the 2 patients with the lowest thymic rebound, responded less well than the patients in whom the number of CD4+CD45RA+RO naive T
cells was higher. Interestingly, the number of naive T cells and the
resulting restoration of the T-cell repertoire correlated better with
the patient's capacity to respond than, eg, the number of
CD4+ T cells, age, or the moment of immunization.
Therefore, the appearance of
CD4+CD45RA+RO T cells after SCT
can be taken as a marker for the reconstitution of the immune response,
which should be of use in scheduling the revaccination
program.
T-cell immune deficiency is responsible for a significant number of late deaths after SCT.34 Apparently, it may take years before T-cell immunity is restored, and particularly in the elderly patient, the pretransplant level may never be achieved. There are several reasons T-cell immunity can be insufficient when all other hematopoietic lineages are functional. First, stem cells produce only T-cell precursors, and in contrast to other hematopoietic lineages, T cells still have to undergo an extensive postmarrow maturation process in the thymus. Most of the T-cell pool is produced around birth, and it is not known whether the adult thymus still has the capacity to regenerate a new repertoire.20,35,36 The process of understanding why immunity is not restored by the T cells that repopulate the patient after SCT has been slow. To date, it has been established that T-cell reconstitution after SCT is not a recapitulation of T-cell ontogeny, but that initially, the T-cell compartment is restored through expansion of mature T cells16 that have survived the conditioning18 or that are cotransfused with the graft.17 Because the expanding T cells do not contain the repertoire needed to respond to common antigens, the risk of infections remains significant notwithstanding the normal number of T cells in the blood. The loss of memory is evident not only in the frequent occurrence
of infections but perhaps even more so in the incapacity of the patient
to respond to vaccinations against classical recall antigens. Once
memory has been lost, it is obvious that a response can be recruited
only from naive cells that have the capacity to recognize the antigen.
In this report, we show that in recipients of a T-cell-depleted graft,
who lack such naive T cells after transplantation, the response to
vaccinations with TT depends entirely on the thymic rebound. This is
further supported by the fact that TT-specific clones were never found
before the appearance of
CD4+CD45RA+RO We have assessed the response to vaccinations with TT by the in vitro proliferative response of TT-specific T cells. This assay gives a good quantitative impression of the response, because it directly reflects the frequency of antigen-specific T cells in the blood. After SCT, this has an advantage over measuring the humoral response, because before vaccination, more than half of the patients still have anti-TT antibodies in the serum.38 In addition, antibody titers may vary more than 50-fold, making it difficult to weigh the significance of the very weak responses. In our group of patients, this also made the interpretation of anti-TT titers difficult. Nevertheless, we observed some correlations between the antibody response and the extent of the thymic rebound at the time of immunization. The 3 patients with the highest numbers of naive cells (patients number 1, 2, and 6) also had the highest antibody titers. In contrast, when the numbers of naive T cells were low and no proliferative response was detected (patients number 8 and 9), even 3 boosts of TT had little effect. Patient number 8 did not respond to the first vaccination, and after the third boost, this patient's titer was the lowest of all the samples tested. Furthermore, the 3 boosts did not induce any change in the antibody titer in patient number 9, who was already positive before vaccination. In conclusion, we have shown that the thymic rebound as measured
by the reappearance of
CD4+CD45RA+RO It has been shown that in long-term survivors, low numbers of
CD4+ cells correlate to high infectious
morbidity.11 It will be interesting to see whether the
increase in the number of
CD4+CD45RA+RO
The authors thank Dr Nathalie Rufer for critical reading of the manuscript and Solange Vischer for excellent technical assistance.
Submitted October 6, 1999; accepted May 14, 2000.
Supported by a grant from the Swiss National Science Foundation (#31-53774.98) and by the Dr Henri Dubois-Ferrière-Dinu Lipatti Foundation.
E.R. and F.D.-G. 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: Eddy Roosnek, Unité d'Immunologie de Transplantation, Hôpital cantonal universitaire de Genève, 24 rue Micheli-du-Crest, CH-1211 Genève 14, Switzerland; e-mail: roosnek{at}cmu.unige.ch.
1.
Kernan NA, Bartsch G, Ash R, et al.
Analysis of 462 transplantations from unrelated donors facilitated by the national marrow donor program.
N Engl J Med.
1993;328:593-602
2.
Davies SM, Shu XO, Blazar BR, et al.
Unrelated donor bone marrow transplantation: influence of HLA A and B incompatibility on outcome.
Blood.
1995;86:1636-1642 3. Horowitz MM, Rowlings PA. An update from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry on current activity in hematopoietic stem cell transplantation. Curr Opin Hematol. 1997;4:395-400[Medline] [Order article via Infotrieve]. 4. Savage DG, Goldman JM. Allografting for chronic myeloid leukemia. Curr Opin Hematol. 1997;4:369-376[Medline] [Order article via Infotrieve]. 5. Hansen JA, Petersdorf E, Martin PJ, Anasetti C. Hematopoietic stem cell transplants from unrelated donors. Immunol Rev. 1997;157:141-151[Medline] [Order article via Infotrieve]. 6. Gratwohl A, Passweg J, Baldomero H, Hermans J. Blood and marrow transplantation activity in Europe 1996. European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 1998;22:227-240[Medline] [Order article via Infotrieve]. 7. Witherspoon RP, Lum LG, Storb R. Immunologic reconstitution after human marrow grafting. Semin Hematol. 1984;21:2-10[Medline] [Order article via Infotrieve].
8.
Lum LG.
The kinetics of immune reconstitution after human marrow transplantation.
Blood.
1987;69:369-380 9. Martin PJ, Hansen JA, Storb R, Thomas ED. Human marrow transplantation: an immunological perspective. Adv Immunol. 1987;40:379-438[Medline] [Order article via Infotrieve]. 10. Storek J, Witherspoon RP. Immunological reconstitution after hematopoietic stem cell transplantation. In: Atkinson K, ed. Clinical Bone Marrow and Blood Stem Cell Transplantation: A Reference Textbook. Cambridge, UK: Cambridge University Press; 1998:111-146. 11. Storek J, Gooley T, Witherspoon RP, Sullivan KM, Storb R. Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol. 1997;54:131-138[Medline] [Order article via Infotrieve].
12.
Reusser P, Riddell SR, Meyers JD, Greenberg PD.
Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease.
Blood.
1991;78:1373-1380
13.
Lum LG, Munn NA, Schanfield MS, Storb R.
The detection of specific antibody formation to recall antigens after human bone marrow transplantation.
Blood.
1986;67:582-587
14.
Lucas KG, Small TN, Heller G, Dupont B, O'Reilly RJ.
The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation.
Blood.
1996;87:2594-2603
15.
Wang FZ, Dahl H, Linde A, et al.
Lymphotropic herpesviruses in allogeneic bone marrow transplantation.
Blood.
1996;88:3615-3620 16. Rocha B, Dautigny N, Pereira P. Peripheral T lymphocytes: expansion potential and homeostatic regulation of pool sizes and CD4/CD8 ratios in vivo. Eur J Immunol. 1989;19:905-911[Medline] [Order article via Infotrieve].
17.
Mackall CL, Granger L, Sheard MA, Cepeda R, Gress RE.
T-cell regeneration after bone marrow transplantation: differential CD45 isoform expression on thymic-derived versus thymic-independent progeny.
Blood.
1993;82:2585-2594
18.
Mackall CL, Fleisher TA, Brown MR, et al.
Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy.
N Engl J Med.
1995;332:143-149 19. Mackall CL, Hakim FT, Gress RE. T-cell regeneration: all repertoires are not created equal. Immunol Today. 1997;18:245-251[Medline] [Order article via Infotrieve].
20.
Dumont-Girard F, Roux E, Van Lier RA, et al.
Reconstitution of the T cell compartment after bone marrow transplantation: restoration of the repertoire by thymic emigrants.
Blood.
1998;92:4464-4471
21.
Roux E, Helg C, Dumont-Girard F, et al.
Analysis of T cell repopulation after allogeneic bone marrow transplantation: significant differences between recipients of T cell depleted and unmanipulated grafts.
Blood.
1996;87:3984-3992 22. Roux E, Helg C, Chapuis B, Jeannet M, Roosnek E. T-cell repertoire complexity after allogeneic bone marrow transplantation. Hum Immunol. 1996;48:135-138[Medline] [Order article via Infotrieve]. 23. Mackall CL, Hakim FT, Gress RE. Restoration of T-cell homeostasis after T-cell depletion. Semin Immunol. 1997;9:339-346[Medline] [Order article via Infotrieve].
24.
Roux E, Helg C, Chapuis B, Jeannet M, Roosnek E.
Evolution of mixed chimerism after allogeneic bone marrow transplantation as determined on granulocytes and mononuclear cells by the polymerase chain reaction.
Blood.
1992;79:2775-2781
25.
Roux E, Abdi K, Speiser D, et al.
Characterization of mixed chimerism in patients with chronic myeloid leukemia transplanted with T-cell-depleted bone marrow: involvement of different hematologic lineages before and after relapse.
Blood.
1993;81:243-248
26.
Panina Bordignon P, Corradin G, Roosnek E, Sette A, Lanzavecchia A.
Recognition by class II alloreactive T cells of processed determinants from human serum proteins.
Science.
1991;252:1548-1550
27.
Hale G, Zhang MJ, Bunjes D, et al.
Improving the outcome of bone marrow transplantation by using CD52 monoclonal antibodies to prevent graft-versus-host disease and graft rejection.
Blood.
1998;92:4581-4590
28.
Arlettaz L, Barbey C, Dumont-Girard F, et al.
CD45 isoform phenotypes of human T cells: CD4+CD45RA
29.
Small TN, Papadopoulos EB, Boulad F, et al.
Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions.
Blood.
1999;93:467-480
30.
Hamann D, Kostense S, Wolthers KC, et al.
Evidence that human CD8+CD45RA+CD27
31.
Heitger A, Neu N, Kern H, et al.
Essential role of the thymus to reconstitute naive (CD45RA+) T-helper cells after human allogeneic bone marrow transplantation.
Blood.
1997;90:850-857 32. Ljungman P, Cordonnier C, De Bock R, et al. Immunisations after bone marrow transplantation: results of a European survey and recommendations from the infectious diseases working party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 1995;15:455-460[Medline] [Order article via Infotrieve]. 33. Somani J, Larson RA. Reimmunization after allogeneic bone marrow transplantation. Am J Med. 1995;98:389-398[Medline] [Order article via Infotrieve].
34.
Socie G, Stone JV, Wingard JR, et al.
Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry.
N Engl J Med.
1999;341:14-21 35. Mackall CL, Gress RE. Thymic aging and T-cell regeneration. Immunol Rev. 1997;160:91-102[Medline] [Order article via Infotrieve].
36.
Poulin JF, Viswanathan MN, Harris JM, et al.
Direct evidence for thymic function in adult humans.
J Exp Med.
1999;190:479-486 37. Weinberg K, Annett G, Kashyap A, et al. The effect of thymic function on immunocompetence following bone marrow transplantation. Biol Blood Marrow Transplant. 1995;1:18-23[Medline] [Order article via Infotrieve]. 38. Hammarström V, Pauksen K, Björkstrand B, et al. Tetanus immunity in autologous bone marrow and blood stem cell transplant recipients. Bone Marrow Transplant. 1998;22:67-71[Medline] [Order article via Infotrieve].
© 2000 by The American Society of Hematology.
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|
  E. Clave, M. Busson, C. Douay, R. Peffault de Latour, J. Berrou, C. Rabian, M. Carmagnat, V. Rocha, D. Charron, G. Socie, et al. Acute graft-versus-host disease transiently impairs thymic output in young patients after allogeneic hematopoietic stem cell transplantation Blood, June 18, 2009; 113(25): 6477 - 6484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Opiela, T. Koru-Sengul, and B. Adkins Murine neonatal recent thymic emigrants are phenotypically and functionally distinct from adult recent thymic emigrants Blood, May 28, 2009; 113(22): 5635 - 5643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sacre, S. Nguyen, C. Deback, G. Carcelain, J.-P. Vernant, V. Leblond, B. Autran, and N. Dhedin Expansion of Human Cytomegalovirus (HCMV) Immediate-Early 1-Specific CD8+ T Cells and Control of HCMV Replication after Allogeneic Stem Cell Transplantation J. Virol., October 15, 2008; 82(20): 10143 - 10152. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Sutherland, L. Spyroglou, J. L. Muirhead, T. S. Heng, A. Prieto-Hinojosa, H. M. Prince, A. P. Chidgey, A. P. Schwarer, and R. L. Boyd Enhanced Immune System Regeneration in Humans Following Allogeneic or Autologous Hemopoietic Stem Cell Transplantation by Temporary Sex Steroid Blockade Clin. Cancer Res., February 15, 2008; 14(4): 1138 - 1149. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Seggewiss, K. Lore, F. J. Guenaga, S. Pittaluga, J. Mattapallil, C. K. Chow, R. A. Koup, K. Camphausen, M. C. Nason, M. Meier-Schellersheim, et al. Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques. Blood, July 1, 2007; 110(1): 441 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gorski, X. Chen, M. Gendelman, M. Yassai, A. Krueger, E. Tivol, B. Logan, R. Komorowski, S. Vodanovic-Jankovic, and W. R. Drobyski Homeostatic expansion and repertoire regeneration of donor T cells during graft versus host disease is constrained by the host environment Blood, June 15, 2007; 109(12): 5502 - 5510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Hauri-Hohl, M. P. Keller, J. Gill, K. Hafen, E. Pachlatko, T. Boulay, A. Peter, G. A. Hollander, and W. Krenger Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation Blood, May 1, 2007; 109(9): 4080 - 4088. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. W. Rossi, L. T. Jeker, T. Ueno, S. Kuse, M. P. Keller, S. Zuklys, A. V. Gudkov, Y. Takahama, W. Krenger, B. R. Blazar, et al. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells Blood, May 1, 2007; 109(9): 3803 - 3811. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. van Laar and A. Tyndall Adult stem cells in the treatment of autoimmune diseases Rheumatology, October 1, 2006; 45(10): 1187 - 1193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Appay, C. Jandus, V. Voelter, S. Reynard, S. E. Coupland, D. Rimoldi, D. Lienard, P. Guillaume, A. M. Krieg, J.-C. Cerottini, et al. New Generation Vaccine Induces Effective Melanoma-Specific CD8+ T Cells in the Circulation but Not in the Tumor Site J. Immunol., August 1, 2006; 177(3): 1670 - 1678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chalandon, S. Degermann, J. Villard, L. Arlettaz, L. Kaiser, S. Vischer, S. Walter, M. H. M. Heemskerk, R. A. W. van Lier, C. Helg, et al. Pretransplantation CMV-specific T cells protect recipients of T-cell-depleted grafts against CMV-related complications Blood, January 1, 2006; 107(1): 389 - 396. [Abstract] [Full Text] [PDF]
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 J. Baner, P. Marits, M. Nilsson, O. Winqvist, and U. Landegren Analysis of T-Cell Receptor V{beta} Gene Repertoires after Immune Stimulation and in Malignancy by Use of Padlock Probes and Microarrays Clin. Chem., April 1, 2005; 51(4): 768 - 775. [Abstract] [Full Text] [PDF]
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C. J. Workman and D. A. A. Vignali Negative Regulation of T Cell Homeostasis by Lymphocyte Activation Gene-3 (CD223) J. Immunol., January 15, 2005; 174(2): 688 - 695. [Abstract] [Full Text] [PDF]
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 S. Samira, C. Ferrand, A. Peled, A. Nagler, Y. Tovbin, H. Ben-Hur, N. Taylor, A. Globerson, and T. Lapidot Tumor Necrosis Factor Promotes Human T-Cell Development in Nonobese Diabetic/Severe Combined Immunodeficient Mice Stem Cells, November 1, 2004; 22(6): 1085 - 1100. [Abstract] [Full Text] [PDF]
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W. Krenger, H. Schmidlin, G. Cavadini, and G. A. Hollander On the Relevance of TCR Rearrangement Circles as Molecular Markers for Thymic Output during Experimental Graft-versus-Host Disease J. Immunol., June 15, 2004; 172(12): 7359 - 7367. [Abstract] [Full Text] [PDF]
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D. Montagna, F. Locatelli, A. Moretta, D. Lisini, C. Previdere, P. Grignani, P. DeStefano, G. Giorgiani, E. Montini, S. Pagani, et al. T lymphocytes of recipient origin may contribute to the recovery of specific immune response toward viruses and fungi in children undergoing cord blood transplantation Blood, June 1, 2004; 103(11): 4322 - 4329. [Abstract] [Full Text] [PDF]
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E. Chklovskaia, P. Nowbakht, C. Nissen, A. Gratwohl, M. Bargetzi, and A. Wodnar-Filipowicz Reconstitution of dendritic and natural killer-cell subsets after allogeneic stem cell transplantation: effects of endogenous flt3 ligand Blood, May 15, 2004; 103(10): 3860 - 3868. [Abstract] [Full Text] [PDF]
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P. Ljungman, R. Brand, H. Einsele, F. Frassoni, D. Niederwieser, and C. Cordonnier Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis Blood, December 15, 2003; 102(13): 4255 - 4260. [Abstract] [Full Text] [PDF]
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J.-F. Poulin, M. Sylvestre, P. Champagne, M.-L. Dion, N. Kettaf, A. Dumont, M. Lainesse, P. Fontaine, D.-C. Roy, C. Perreault, et al. 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, December 15, 2003; 102(13): 4600 - 4607. [Abstract] [Full Text] [PDF]
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M. K. Gandhi, M. R. Wills, G. Okecha, E. K. Day, R. Hicks, R. E. Marcus, J. G. P. Sissons, and A. J. Carmichael Late diversification in the clonal composition of human cytomegalovirus-specific CD8+ T cells following allogeneic hemopoietic stem cell transplantation Blood, November 1, 2003; 102(9): 3427 - 3438. [Abstract] [Full Text] [PDF]
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N. Rufer, A. Zippelius, P. Batard, M. J. Pittet, I. Kurth, P. Corthesy, J.-C. Cerottini, S. Leyvraz, E. Roosnek, M. Nabholz, et al. Ex vivo characterization of human CD8+ T subsets with distinct replicative history and partial effector functions Blood, September 1, 2003; 102(5): 1779 - 1787. [Abstract] [Full Text] [PDF]
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A. E. C. Broers, S. J. Posthumus-van Sluijs, H. Spits, B. van der Holt, B. Lowenberg, E. Braakman, and J. J. Cornelissen Interleukin-7 improves T-cell recovery after experimental T-cell-depleted bone marrow transplantation in T-cell-deficient mice by strong expansion of recent thymic emigrants Blood, August 15, 2003; 102(4): 1534 - 1540. [Abstract] [Full Text] [PDF]
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 E. Orsini, R. Bellucci, E. P. Alyea, R. Schlossman, C. Canning, S. McLaughlin, P. Ghia, K. C. Anderson, and J. Ritz Expansion of Tumor-specific CD8+ T Cell Clones in Patients with Relapsed Myeloma after Donor Lymphocyte Infusion Cancer Res., May 15, 2003; 63(10): 2561 - 2568. [Abstract] [Full Text] [PDF]
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M. Sarzotti, D. D. Patel, X. Li, D. A. Ozaki, S. Cao, S. Langdon, R. E. Parrott, K. Coyne, and R. H. Buckley T Cell Repertoire Development in Humans with SCID After Nonablative Allogeneic Marrow Transplantation J. Immunol., March 1, 2003; 170(5): 2711 - 2718. [Abstract] [Full Text] [PDF]
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 G. Mufti, A. F. List, S. D. Gore, and A. Y.L. Ho Myelodysplastic Syndrome Hematology, January 1, 2003; 2003(1): 176 - 199. [Abstract] [Full Text] [PDF]
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N. Dainiak, J. K. Waselenko, J. O. Armitage, T. J. MacVittie, and A. M. Farese The Hematologist and Radiation Casualties Hematology, January 1, 2003; 2003(1): 473 - 496. [Abstract] [Full Text] [PDF]
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S. R. Lewin, G. Heller, L. Zhang, E. Rodrigues, E. Skulsky, M. R. M. van den Brink, T. N. Small, N. A. Kernan, R. J. O'Reilly, D. D. Ho, et al. Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantations Blood, August 28, 2002; 100(6): 2235 - 2242. [Abstract] [Full Text] [PDF]
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M. Eyrich, T. Croner, C. Leiler, P. Lang, P. Bader, T. Klingebiel, D. Niethammer, and P. G. Schlegel Distinct contributions of CD4+ and CD8+ naive and memory T-cell subsets to overall T-cell-receptor repertoire complexity following transplantation of T-cell-depleted CD34-selected hematopoietic progenitor cells from unrelated donors Blood, August 13, 2002; 100(5): 1915 - 1918. [Abstract] [Full Text] [PDF]
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S. Rossi, B. R. Blazar, C. L. Farrell, D. M. Danilenko, D. L. Lacey, K. I. Weinberg, W. Krenger, and G. A. Hollander Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease Blood, June 28, 2002; 100(2): 682 - 691. [Abstract] [Full Text] [PDF]
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M. Guimond, A. Balassy, M. Barrette, S. Brochu, C. Perreault, and D. C. Roy P-glycoprotein targeting: a unique strategy to selectively eliminate immunoreactive T cells Blood, June 28, 2002; 100(2): 375 - 382. [Abstract] [Full Text] [PDF]
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R. Bellucci, E. P. Alyea, E. Weller, A. Chillemi, E. Hochberg, C. J. Wu, C. Canning, R. Schlossman, R. J. Soiffer, K. C. Anderson, et al. Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma Blood, May 29, 2002; 99(12): 4610 - 4617. [Abstract] [Full Text] [PDF]
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P. Ye and D. E. Kirschner Reevaluation of T Cell Receptor Excision Circles as a Measure of Human Recent Thymic Emigrants J. Immunol., May 15, 2002; 168(10): 4968 - 4979. [Abstract] [Full Text] [PDF]
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M. Di Nicola, C. Carlo-Stella, M. Magni, M. Milanesi, P. D. Longoni, P. Matteucci, S. Grisanti, and A. M. Gianni Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli Blood, May 15, 2002; 99(10): 3838 - 3843. [Abstract] [Full Text] [PDF]
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A. Heitger, P. Winklehner, P. Obexer, J. Eder, C. Zelle-Rieser, G. Kropshofer, M. Thurnher, and W. Holter Defective T-helper cell function after T-cell-depleting therapy affecting naive and memory populations Blood, May 13, 2002; 99(11): 4053 - 4062. [Abstract] [Full Text] [PDF]
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M. D. Hazenberg, S. A. Otto, E. S. de Pauw, H. Roelofs, W. E. Fibbe, D. Hamann, and F. Miedema T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events Blood, May 1, 2002; 99(9): 3449 - 3453. [Abstract] [Full Text] [PDF]
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K. Talvensaari, E. Clave, C. Douay, C. Rabian, L. Garderet, M. Busson, F. Garnier, D. Douek, E. Gluckman, D. Charron, et al. 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, February 15, 2002; 99(4): 1458 - 1464. [Abstract] [Full Text] [PDF]
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V. T. Ho and R. J. Soiffer The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation Blood, December 1, 2001; 98(12): 3192 - 3204. [Full Text] [PDF]
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J. L. Cohen, O. Boyer, and D. Klatzmann Suicide gene therapy of graft-versus-host disease: immune reconstitution with transplanted mature T cells Blood, October 1, 2001; 98(7): 2071 - 2076. [Abstract] [Full Text] [PDF]
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 A. R.M. Almeida, J. A.M. Borghans, and A. A. Freitas T Cell Homeostasis: Thymus Regeneration and Peripheral T Cell Restoration in Mice with a Reduced Fraction of Competent Precursors J. Exp. Med., August 27, 2001; 194(5): 591 - 600. [Abstract] [Full Text] [PDF]
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E. P. Hochberg, A. C. Chillemi, C. J. Wu, D. Neuberg, C. Canning, K. Hartman, E. P. Alyea, R. J. Soiffer, S. A. Kalams, and J. Ritz Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults Blood, August 15, 2001; 98(4): 1116 - 1121. [Abstract] [Full Text] [PDF]
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N. Rufer, T. H. Brummendorf, B. Chapuis, C. Helg, P. M. Lansdorp, and E. Roosnek Accelerated telomere shortening in hematological lineages is limited to the first year following stem cell transplantation Blood, January 15, 2001; 97(2): 575 - 577. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
cells are induced by antigen and evolve through extensive rounds of division.
Int Immunol.
1999;11:1027-1033