Assessment of the Effect of Nilotinib (Tasigna) Maintenance Therapy After Allogeneic Stem Cell Transplantation in Patients with Advanced CML and Ph+ ALL On Immune Reconstitution and Lymphocyte Function

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4478-4478
Author(s):  
Nira Varda-Bloom ◽  
Raz Somech ◽  
Yulia Volchek ◽  
Jacqueline Davidson ◽  
Atar Lev ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Immune Reconstitution ◽  
Lymphocyte Subsets ◽  
Chronic Gvhd ◽  
Mitogenic Response ◽  
Tcr Repertoire ◽  
And Function

Abstract Abstract 4478 Allogeneic stem cell transplantation (AlloSCT) is the treatment of choice in advanced chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL). However, post transplant relapse rate is high and outcome is often poor in this setting. Reduction of tumor mass pre-transplant and maintenance therapy post alloSCT, may improve response rate and reduce relapse rate. We speculated that the second-generation tyrosine-kinase inhibitor (TKI) Nilotinib (Tasigna, Novartis Pharmaceuticals) would be effective in achieving these goals. In the current study Nilotinib, was administered as maintenance therapy post alloSCT in patients (pts) with advanced CML and Ph+ ALL (study CAMN107AIL03T). However, TKIs have been demonstrated in previously published literature to affect T cells proliferation and signal transduction and to potentiate LGL and NK cell activity. Furthermore, in recent studies TKIs have also been demonstrated to ameliorate chronic GVHD. We therefore assessed immunological reconstitution and function including flow analysis of lymphocyte subsets, T-mitogenic response to αCD3 and PHA, thymic activity as determined by the quantification of the T cell receptor excision circles (TREC), TCR repertoire and NK cells cytotoxic activity against K562 cell line. In all, the study included 24 pts. Patients engrafted in a median day +15 (range, 10–38) with 100% donor chimerism. Acute GVHD grade 3/4 was reported in 3 pts (14%) and the rate of extensive chronic GVHD at last follow up was 50%. At 6 months after alloSCT, 11 of 15 pts with advanced CML had attained CCyR, 11 of 15 pts with advanced CML had attained a MMR or better, and 5 of 7 pts with Ph+ ALL attained a CR. The median OS was 16 months, with predicted 1- and 2- year rates of 55% (95% CI, 32% – 72%) and 50% (95% CI, 28% – 68%), respectively. The median PFS was 11 months, with predicted 1- and 2- year rates of 50% (95% CI, 28% – 68%) and 38% (95% CI, 17% – 59%), respectively. Immunological testing was performed pre- and post Nilotinib maintenance therapy in 12 pts (advanced CML-8, Ph+ ALL-4) who received Nilotinib for at least 90 days following alloSCT. The median age was 34.5 years (range, 21–57) and 75% were males. Six pts underwent alloSCT from an HLA-matched sibling donor, 4 from matched unrelated and 2 from an alternative donor (cord blood-1, haploidentical-1). All had myeloablative conditioning. GVHD prophylaxis included CSA and MMF. The relative percentage of T- lymphocyte subsets (assessed by FACS) and total lymphocytes number were stable during Nilotinib maintenance administration after alloSCT, while a 7.8±2.5 fold increase in B cells was noted. T cell mitogenic response with αCD3 and PHA (stimulation index ratio) was sustained (2.5±1.0, vs. 2.8±1.05 and 3.3±1.3 vs. 5.3±2.9 stimulation, pre- and post Nilotinib therapy, respectively). Mean thymic output determined by TREC quantification pre-, during and post Nilotinib administration was 81.8±108, 81.2±90.3 and 142.8±197.4 copies per 0.5ug DNA indicating continuous thymopoiesis. Similarly, no significant change of the TCR repertoire was observed during Nilotinib treatment. Specifically, normal expression of the TCR repertoire was detected in 15.1±5.5 and 15.3±5.6 of the examined TCRs, clonal expression was detected in 2.5±2.2 and 2.9±3 of the examined receptors, while reduced expression was detected only in 6.4±4.3 and 5.8±4.5 of the examined receptors pre-and post Nilotinib treatment, respectively. NK cytotoxic activity against K562 expressed as fold of change from baseline, also remained stable during Nilotinib treatment (2.8±1.1 and 2.3±0.8, respectively). In summary, Nilotinib maintenance therapy post alloSCT in pts with advanced CML and Ph+ALL did not interfere or jeopardized immune reconstitution and function including the number of immune cell subsets, T cell mitogenic response, TCR repertoire, thymic output and NK cytolytic activity post alloSCT. Based on this immunological data we would further recommend Nilotinib maintenance therapy post alloSCT in pts with advanced CML and Ph+ALL. Disclosures: Nagler: Novartis: Honoraria, Research Funding.

Haploidentical Stem Cell Transplantation: High Doses of Alloreactive-T Cell Depleted Donor Lymphocytes Administered Post-Transplant Decrease Infections and Improve Survival without Causing Severe Gvhd.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 512-512 ◽  
Author(s):  
Denis-Claude Roy ◽  
Silvy Lachance ◽  
Thomas Kiss ◽  
Sandra Cohen ◽  
Lambert Busque ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Chronic Gvhd ◽  
T Cell Depletion ◽  
Post Transplant

Abstract Abstract 512 Delayed immune reconstitution following intensive T cell depletion of the stem cell graft is the main complication limiting broad utilization of haplo-mismatched donors for stem cell transplantion (SCT). Indeed, it results in frequent and rapidly lethal infectious events. The ability to accelerate immune reconstitution following haplo-SCT would provide a unique opportunity to transplant the large number of patients who cannot find an HLA-matched donor. We present results of our Phase I clinical trial of haploidentical allogeneic SCT followed by an “add-back of donor T cells to accelerate immune reconstitution” (ATIR). This donor lymphocyte infusion (DLI) underwent photodynamic depletion (PD) of host-reactive T cells using dibromorhodamine as photosensitizer (Kiadis Pharma). Nineteen patients (11 M, 8 F) with very high-risk hematologic malignancies (mostly refractory or relapsed acute myeloid leukemia (10) and myelodysplastic syndromes (4), and refractory ALL (1), CLL (2), CML (1) and NHL (1)) entered the trial. Median age at SCT was 54 years (range: 19-62). HLA compatibility was 3/6 in 6 pts, 4/6 in 12 pts and 5/6 (DR mismatch) in 1 pt. Increasing doses of PD-treated donor cells (ATIR: 1×104 to 5.0 ×106 CD3+ cells/kg) were administered on day 34±6 after transplant. In the ATIR, greater than 95% of CD4+CD25+ and CD8+CD25+ T cells as well as anti-host cytotoxic T lymphocyte precursors (CTLp) were depleted from DLIs. All stem cell grafts underwent in vitro immunomagnetic T cell depletion using CD34+ positive cell selection (Miltenyi). The myeloablative regimen consisted of TBI (1200 cGy), thiotepa (5 mg/kg) and fludarabine (200 mg/m2). No GVHD prophylaxis was administered. All patients showed complete donor chimerism and durable hematologic engraftment. Five patients developed grade II GVHD affecting skin (n = 5 pts), liver (2 pts) and gastrointestinal tract (1 pt) at a median of 101 days post-SCT. No patient developed grade III-IV acute GVHD. Chronic GVHD developed in 9 pts, mostly in those receiving higher T cell doses. Treatment of acute and chronic GVHD involved steroids, tacrolimus and mycophenolate mofetil in 3 patients, steroids and tacrolimus in 3 pts, and steroids only in 3 pts. GVHD responded rapidly to treatment since the median duration of total immunosuppressive therapy in each patient was 187 days (range: 61-319 d). All 7 patients in cohorts 1-3, who received 1.3×105 or less CD3+ cells/kg, developed infectious complications (100% of pts), with 5 lethal episodes in these 7 pts. In sharp contrast, only 6 (50%) of the following 12 patients (cohorts 4-7) receiving ATIR with the highest CD3+ cell doses (3.2×105 to 5.0×106 CD3+ cells/kg) developed infections (p <0.05), none resulting in a fatal event (p<0.001). Interestingly, CD3 lymphocytes recovered earlier in the last 2 cohorts (6 and 7) receiving 2-5×106 CD3+ cells/kg than in the first 5 cohorts (7.9×105 or less CD3+ cells/kg) (p<0.01). Eight patients died: 4 of relapsed leukemia (3 AML; 1 ALL) and 4 of infections. Overall treatment related mortality (TRM) is 27% at 2 years post-SCT, with a TRM of 0% in patients receiving the highest CD3+ cell doses (cohorts 4-7). The overall survival is 60% at 2 years (median f-up: 12.1 mo; 95% confidence interval at 2 years: 37-83%). The 12 patients in cohorts 4-7 receiving the higher CD3+ cell doses had an improved survival (82% at 2 yrs) over the 7 patients in cohorts 1-3 administered a lower CD3+ cell dose (14% at 2 yrs) (p<0.05). Our results indicate that the post-transplant infusion of an ATIR-PD treated DLI is feasible, results in accelerated T cell reconstitution, and decreases the incidence and severity of infections without inducing severe GVHD. These results suggest a clinical benefit for patients receiving the highest ATIR doses and form the basis of an international pivotal clinical trial to decrease TRM in patients undergoing haploidentical stem cell transplantation. Disclosures: Roy: Kiadis Pharma: Research Funding. Egeler:Kiadis Pharma: Employment.

scholarly journals Identification of Lymphocyte Subsets Associated with Outcomes in Patients with Hematological Malignancy Following Allogeneic Stem Cell Transplantation: A Single Institute Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2115-2115
Author(s):  
Taiki Ando ◽  
Yasufumi Ishiyama ◽  
Takayoshi Tachibana ◽  
Masatsugu Tanaka ◽  
Heiwa Kanamori ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Nk Cells ◽  
Immune Reconstitution ◽  
Lymphocyte Subsets ◽  
Chronic Gvhd ◽  
T Cell Subsets ◽  
Transplant Outcome ◽  
Cell Sources

Abstract Background: Immune reconstitution after allogeneic stem cell transplantation (SCT) is a complicated process influenced by factors such as preconditioning regimens, graft-versus-host disease (GVHD) prophylaxis, and grafts. We studied the association between the kinetics of lymphocyte subsets and transplant outcome to clarify the differences in immune reconstitution after hematopoietic cell transplantation according to stem cell sources and its clinical significance. Patients and Methods: Clinical data were collected from patients' medical charts at Kanagawa Cancer Center, Yokohama, Japan. Patients with hematological malignancies aged ≥18 years old who underwent SCT between April 2009 and December 2017 were initially selected. Those who died or experienced disease relapse before day 100 post SCT were excluded. We measured absolute lymphocyte count (ALC) and lymphocyte subsets by flow cytometry with antibodies against CD2, CD3, CD4, CD8, CD11b, CD11c, CD16, CD25, CD29, CD56, CD57, CD45RA, and CD45RO on days 100, 180, 365, and 730 post SCT. Results: The final cohort included 314 patients (acute leukemia, n = 249; myelodysplastic syndrome, n = 44; chronic myelogenous leukemia, n = 9; malignant lymphoma, n = 6; and others, n = 6). The median age was 51 (range: 18- 69) years, with 184 males and 130 females. The disease risk at transplantation was standard in 209 and high in 105 patients. Myeloablative preconditioning was administered to 114 and reduced-intensity preconditioning to 200 patients. Bone marrow transplantation (BMT), peripheral blood SCT (PBSCT), and cord blood transplantation (CBT) were performed in 121, 57, and 136 patients, respectively. A calcineurin inhibitor with short-term methotrexate was mainly used for GVHD prevention. The median follow-up of surviving patients was 869 (range: 103-3074) days. The 2-year overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) in BMT, PBSCT, and CBT were 62%, 68%, and 76% (P = 0.023); 33%, 38%, and 27% (P = 0.068); and 17%, 16%, and 13% (P = 0.82); respectively. The 2-year cumulative incidence of chronic GVHD was 43% in BMT, 45% in PBSCT, and 28% in CBT (P = 0.027). There were significant differences between lymphocyte subset recovery and stem cell sources (Table). ALC; CD20+ B cell; CD4+, CD4+CD29+, CD4+CD45RO+, CD4+CD45RO− , and CD4+CD45RA+ T cell subsets; and CD3−CD56+ and CD16+CD57− natural killer (NK) cell subsets were significantly elevated in CBT compared with BMT and PBSCT at day 100 post SCT. Conversely, CD8+CD11b+ and CD8+CD11b− T cell subsets and CD3+CD56+ NKT cells were significantly lower in CBT than in BMT and PBSCT on day 100. Univariate analysis revealed that lymphocyte subsets exhibiting higher levels of CD20+ B cell; CD16+CD57− and CD3−CD56+ NK cells; and CD4+CD25+, CD4+CD29+, CD4+CD45RA+, CD8+CD11b+, and CD8+CD11b− T cell subsets at day 100 were associated with a better 2-year OS. There were strong correlations with a lower CIR and higher CD16+CD57+ and CD16+CD57− NK cell levels . A higher incidence of chronic GVHD was associated with lower levels of CD16+CD57− NK cells and CD4+CD25+ T cells and with higher levels of CD8+CD11b+ T cells and CD8+CD11b− and CD3+CD56+ NKT cells. Further, a lower NRM correlated with higher levels of CD20+ B cells and CD8+CD11b− T cells. The lymphocyte subsets were used for multivariate analysis. Favorable factors for better OS were higher levels of CD16+CD57− NK cells [hazard ratio (HR), 0.62; 95% confidence index (CI), 0.38-0.81; P = 0.024] and CD20+ B cells (HR, 0.56; 95% CI, 0.31-0.0.98; P = 0.048). Prognostic factors for lower CIR were higher levels of CD16+CD57+ NK cells (HR, 0.51; 95% CI, 0.27-0.95; P = 0.034) and CD16+CD57− NK cells (HR, 0.52; 95% CI, 0.28-0.99; P = 0.048). A lower incidence of NRM was associated with higher levels of CD8+CD11b− T cells (HR, 0.18; 95% CI, 0.08-0.39; P < 0.001) and CD20+ B cells (HR, 0.24; 95% CI, 0.08-0.70; P = 0.0088). High levels of CD8+CD11b+ T cells were an independent predictor for a higher incidence of chronic GVHD (HR, 2.38; 95% CI, 1.22-4.95; P = 0.012). Conclusions: The distinct differences in immune reconstitution according to stem cell sources and lymphocyte subset analysis at day 100 post SCT are useful for predicting transplant outcome. Furthermore, the results suggest that characteristic immune recovery in CBT positively affects transplant outcome. Disclosures No relevant conflicts of interest to declare.

Phase 1 Clinical Study of Adoptive Immunotherapy with Delayed Infusion of Alloanergized Donor T Cells to Improve Immune Reconstution after Haploidentical Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1156-1156
Author(s):  
Jeff Davies ◽  
Marcos De Lima ◽  
Laurence Cooper ◽  
Thomas Spitzer ◽  
Neena Kapoor ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Chronic Gvhd ◽  
Optimal Dose ◽  
Effector Memory ◽  
Donor T Cells

Abstract Haploidentical related donors extend availability of hematopoietic stem-cell transplantation (HSCT) to patients (pts) lacking HLA-matched family donors, but profound T-cell depletion (TCD) is needed to prevent severe GvHD, thus delaying immune reconstitution and increasing infection. Adoptive transfer of alloanergized donor T cells is an attractive approach to reconstituting T cell number and function with concomitant GVHD abrogation. We established proof-of-principle in haploidentical bone marrow (BM) transplant trials using ex vivo induction of recipient alloantigen-specific anergy in T cells within donor BM by allostimulation with blockade of CD28-mediated costimulation. This strategy permitted infusion of large doses of haploidentical T cells with donor BM, resulting in rapid immune reconstitution without excess severe GvHD or chronic GVHD. However the optimal dose of alloanergized donor T cells and their impact on functional antigen-specific immune reconstitution were not determined in our prior studies. We now report the results to date of a new study evaluating delayed infusion of escalating doses of donor PBMC anergized to recipient alloantigens after haploidentical HSCT. Alloanergized PBMCs were generated by co-culture of irradiated stimulator PBMC from a second haploidentical related donor (or the pt) using clinical grade humanized monoclonal anti-B7.1 and –B7.2 antibodies. 7 adults (median age 41, range 22–50) and 4 children (median age 7.5, range 2–14) with high risk leukemia/MDS (8 AML (3 CR1 4 CR2, 1 persistent disease), 2 high-IPSS MDS and 1 ALL (CR2) have been treated. Pts received fractionated TBI (1200cGy, n=5) or melphalan (140mg/m2, n=6), fludarabine, thiotepa and ATG followed by CliniMacs CD34-selected peripheral blood stem cells (PBSC) from haploidentical family donors without subsequent pharmacologic GVHD prophylaxis. Median infused cell doses (x 106/kg) were 9.4 (CD34+) and 0.02 (CD3+). All pts engrafted and attained full donor chimerism, with rapid neutrophil and platelet recovery (median D+11 and D+12, respectively). Using novel Bayesian phase I/II adaptive design, 10 pts have received donor PBMC after alloanergization (which resulted in a median 6-fold reduction in alloresponses): Dose (Ds)1, 103 CD3+ cells/kg (n=4), Ds2 104/kg (n=3) and Ds3 105/kg (n=3), infused on D+35 (n=8) or D+42 (n=2) without developing severe acute GvHD (Table). None of 5 evaluable pts developed chronic GvHD. At median follow-up of 8 months (range 1–23), 8/11 pts are alive. 6/11 pts are disease-free. 3 pts have died, from bacterial sepsis (Day +32), pulmonary veno-occlusive disease (D+59), and idiopathic pulmonary syndrome (D+78). Two AML pts have relapsed. Infusion of alloanergized donor PBMC appears to influence reconstitution of both CD4 T cell numbers and functional pathogen-specific T cells (Table). Normal SEB responses and functional CMV- and VZV-specific CD4 and CD8 T cells became detectable at 6–9 months in pts at Ds1, at 3 months in pts at Ds2 and at 2 months in the assessable pt at Ds3. Recovering T cells had a predominantly effector memory phenotype consistent with peripheral expansion of infused alloanergized donor T cells. These data suggest that delayed infusion of modest doses of alloanergized donor PBMC after haploidentical HSCT is not associated with significant GVHD, and may be associated with a dose-dependent improvement of quantitative and qualitative immune reconstitution. Ongoing recruitment of patients to higher alloanergized PBMC dose levels (up to 107/kg if tolerated) will determine the optimal dose that benefits immune reconstitution without causing severe GVHD. Infusion of Alloanergized PBMC GvHD New CMV reactivation Dose Level Pts T cell dose/kg Acute (Grade) Chronic Before PBMC infusion After PBMC infusion EBV/HSV infection after PBMC infusion Median time to CD4 ct &gt;100** (months) Months to detectable CMV/VZV IFN-gamma + T cells * only one evaluable pt at this time, TBD; to be determined: ** cells/microliter 1 4 103 0/4 0/2 2/4 0/4 2/4 9 6-9 2 3 104 1/3 (2) 0/3 2/3 0/3 0/3 4 3 3 3 105 1/3 (1) TBD 1/3 0/3 0/3 2* 2*

New Developments in Allotransplant Immunology

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 350-371 ◽  
Author(s):  
A. John Barrett ◽  
Katayoun Rezvani ◽  
Scott Solomon ◽  
Anne M. Dickinson ◽  
Xiao N. Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Cytokine Gene ◽  
Post Transplant ◽  
Cytokine Milieu ◽  
Cytokine Gene Polymorphisms

Abstract After allogeneic stem cell transplantation, the establishment of the donor’s immune system in an antigenically distinct recipient confers a therapeutic graft-versus-malignancy effect, but also causes graft-versus-host disease (GVHD) and protracted immune dysfunction. In the last decade, a molecular-level description of alloimmune interactions and the process of immune recovery leading to tolerance has emerged. Here, new developments in understanding alloresponses, genetic factors that modify them, and strategies to control immune reconstitution are described. In Section I, Dr. John Barrett and colleagues describe the cellular and molecular basis of the alloresponse and the mechanisms underlying the three major outcomes of engraftment, GVHD and the graft-versus-leukemia (GVL) effect. Increasing knowledge of leukemia-restricted antigens suggests ways to separate GVHD and GVL. Recent findings highlight a central role of hematopoietic-derived antigen-presenting cells in the initiation of GVHD and distinct properties of natural killer (NK) cell alloreactivity in engraftment and GVL that are of therapeutic importance. Finally, a detailed map of cellular immune recovery post-transplant is emerging which highlights the importance of post-thymic lymphocytes in determining outcome in the critical first few months following stem cell transplantation. Factors that modify immune reconstitution include immunosuppression, GVHD, the cytokine milieu and poorly-defined homeostatic mechanisms which encourage irregular T cell expansions driven by immunodominant T cell–antigen interactions. In Section II, Prof. Anne Dickinson and colleagues describe genetic polymorphisms outside the human leukocyte antigen (HLA) system that determine the nature of immune reconstitution after allogeneic stem cell transplantation (SCT) and thereby affect transplant outcomethrough GVHD, GVL, and transplant-related mortality. Polymorphisms in cytokine gene promotors and other less characterized genes affect the cytokine milieu of the recipient and the immune reactivity of the donor. Some cytokine gene polymorphisms are significantly associated with transplant outcome. Other non-HLA genes strongly affecting alloresponses code for minor histocompatibility antigens (mHA). Differences between donor and recipient mHA cause GVHD or GVL reactions or graft rejection. Both cytokine gene polymorphisms (CGP) and mHA differences resulting on donor-recipient incompatibilities can be jointly assessed in the skin explant assay as a functional way to select the most suitable donor or the best transplant approach for the recipient. In Section III, Dr. Nelson Chao describes non-pharmaceutical techniques to control immune reconstitution post-transplant. T cells stimulated by host alloantigens can be distinguished from resting T cells by the expression of a variety of activation markers (IL-2 receptor, FAS, CD69, CD71) and by an increased photosensitivity to rhodamine dyes. These differences form the basis for eliminating GVHD-reactive T cells in vitro while conserving GVL and anti-viral immunity. Other attempts to control immune reactions post-transplant include the insertion of suicide genes into the transplanted T cells for effective termination of GVHD reactions, the removal of CD62 ligand expressing cells, and the modulation of T cell reactivity by favoring Th2, Tc2 lymphocyte subset expansion. These technologies could eliminate GVHD while preserving T cell responses to leukemia and reactivating viruses.

Remission and immune reconstitution after T-cell-depleted stem-cell transplantation for rheumatoid arthritis

The Lancet ◽  
1998 ◽  
Vol 352 (9131) ◽  
pp. 881 ◽  
Author(s):  
Patrick Durez ◽  
Michel Toungouz ◽  
Liliane Schandené ◽  
Micheline Lambermont ◽  
Michel Goldman
Keyword(s):  
Rheumatoid Arthritis ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution

The Elevated Ratio of Peripheral Blood CD27−CD4+ T Cells in Patients Received Allogeneic Stem Cell Transplantation Implies Altered T Cell Homeostasis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1413-1413
Author(s):  
Akiko Fukunaga ◽  
Takayuki Ishikawa ◽  
Takero Shindo ◽  
Sumiko Takao ◽  
Toshiyuki Hori ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Cd4 T Cell ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Effector Cells

Abstract One of the major problems following allogeneic stem cell transplantation (allo-SCT) is the inability to reconstitute an adequate immune system for an extended period. T-cell reconstitution is also delayed for years, especially in CD4+ T cells. In addition to impaired thymic function, shortened Naive T cell survival due to altered T cell homeostasis is reported to be responsible for delayed immune reconstitution. To further investigate the mechanisms of delayed immune recovery after allo-SCT, we focused on the frequencies of effector CD4+ T cells, because according to the previous reports, progressive linear differentiation model of CD4+ T cell predicts the accumulation of terminally differentiated effector cells when transition from naïve to memory T cells and memory to effector cells are accelerated. By flowcytometric analyses we confirmed that CD27−CD4+ T cells from allo-SCT recipients uniformly express CD95, with negative expression of CCR7 and CD62L. They also produce g-interferon (IFNg) in response to the immobilized anti-CD3 and soluble anti-CD28 stimulation, which is consistent with previous reports insisting that CD27−CD4+ T cells are functionally differentiated effector T cells. Measuring the ratio of CD27−CD4+ T cells among CD4+ T cells revealed that, although healthy donors and patients received allo-SCT within a year had comparable CD27+CD4+T-cell rate (90% vs. 83%, P=0.4436), significantly decreased rate was observed in patients transplanted more than 1 year before (55% vs. 83%, P=0.0005). The ratio of CD27+CD4+ T cells kept low during the first 5 years after allo-SCT, and then it slowly begun to increase. In addition, in patients who received stem cell grafts more than 1 year before, the ratio of CD27+CD4+ T cells were significantly higher in patients transplanted from HLA-matched siblings than in those received unrelated grafts (69% vs. 42%, P=0.0002). Other factors, such as stem cell source (BM or PBSC), patient age, and the presence of chronic GVHD did not influence the ratio of CD27+CD4+ T cells. To further investigate the characteristics of CD27−CD4+ T cells in post-transplant periods, peripheral CD4+ T cells from patients who had received allo-SCT more than 1 year before as well as healthy volunteers were sorted into CD27− and CD27+ fractions, stained with CFSE, and stimulated with immobilized anti-CD3 and soluble anti-CD28 antibodies. CD27−CD4+ T cells proliferated more vigorously at 3 days after stimulation, though after another 2-day culture, there was no difference in cell divisions between both cell groups. In addition, CD27+ cells from transplanted patients lost their expression more frequently than those from volunteers, while none of the CD27− cells stored its expression. The fact of one-way transition from CD27+ to CD27− also supported that CD27−CD4+ T cells are terminally differentiated T cells. The finding that the frequencies of CD27−CD4+ T cells begin to elevate at 1 year after allo-SCT indicates that T cells infused with allograft do not easily lose the surface expression of CD27, while T cells derived from donor’s stem cells do. Considering the fact that ratio of CD27−CD4+ T cells is much higher in recipients of unrelated grafts, and it gradually begin to decrease at 5 years after allo-SCT, the increased ratio of CD27−CD4+ T cells may reflect altered T cell homeostasis. The serial monitoring of the ratio of CD27−CD4+ T cells after allo-SCT may be useful in evaluating immune reconstitution status.

The Effect of Costimulatory Moleculars on Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4875-4875
Author(s):  
Zhenhua Qiao ◽  
Fang Ye ◽  
Lei Zu
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Group A ◽  
Group B

Abstract Objective: To explore the effect of costimulatory molecular and CD25 expressed on peripheral CD4+ T lymphocytes on graft-versus-host disease(GVHD) after allogeneic hematopoietic stem cell transplantation(allo-HSCT). Methods: 1. The 21 patients who suffered of hematology diseases or malignant solid tumors and were underwent allo-HSCT and 10 normal individuals were enrolled in the study.2. For the sake of difference conditioning regimens we divided the 21 patients into two groups: patients undergoing non-myeloablative stem cell transplantation(NST) belonged to group A, others undergoing traditional myeloablative stem cell transplantation belonged to group B; we divided them into five groups for with GVHD or without GVHD and types of GVHD: group 1(group A with acute GVHD), group 2(group A with chronic GVHD), group 3(group B with acute GVHD), group 4(group B without GVHD), group 5(group A without GVHD).3. The levels of CD28, CD80, CD152 and CD25 expressions on peripheral CD4+ T lymphocytes were detected by three colors flow cytometry (FCM)in different time(before allo-HSCT,7days,14days,21days,30days after allo-HSCT, the time of GVHD and the time after GVHD treated).4.STR-PCR for detecting micro-satellites chimeras forming. Results: 1. All 21 patients achieved engraftment. By STR-PCR assay,12 cases formed complete chimeras(CC) and 9 cases formed mixed chimeras(MC). In group A,3 cases developed acute GVHD and 4 cases developed chronic GVHD; in group B,4 cases developed aGVHD. The incidence of GVHD and infection rates between group A and B has no difference(X2=3.711, P=0.144).2. Among these 21 cases,5 cases died:2 cases died of multiple organs function failure due to primary disease relapse,1 case died of bleeding in brain and 2 cases died of liver function failure for the sake of complicated with acute GVHD; others survive with disease free till present.3. The results of multivariate logistic regression models and Kaplan-Meier survival curves analyses showed: age, sex, infection, HLA-type, blood type, conditioning regiment and the times of absolute neutrophil counts and platelets recovering to normal, had no association with the incidence of GVHD;A multivariate COX survival function model analysis showed CD4CD152 and CD4CD25 are independent prognostic factors for GVHD(X2=13.128, P<0.0001).4. Patients with GVHD demonstrated higher CD4+CD28+ and CD4+CD80+ T cell levels than those without GVHD(P<0.01);patients with aGVHD demonstrated higher than those with cGVHD(P<0.05) and without GVHD(P<0.05); Patients with GVHD demonstrated lower CD4+CD152+ and CD4+CD25+ T cell levels than those without GVHD(P<0.01); the same result occurs between aGVHD and cGVHD and without GVHD. After effective treatment, unnormal CD4+CD28+, CD4+CD80+, CD4+CD152+ and CD4+CD25+ T cell levels recovered to the levels before transplantation. Conclusions: The incidences of GVHD between NST and traditional myeloablative stem cell transplantation had no difference. B7-CD28/CD152 costimulatory pathway plays a critical role in developing of GVHD. Peripheral CD4+CD28+, CD4+CD80+, CD4+CD152+ and CD4+CD25+ T cell levels were relative to recipient GVHD, especially CD4+CD152+ and CD4+CD25+ T cell levels. Down-grade CD4+CD28+ and CD4+CD80+ T cell levels and up-grade CD4+CD152+ and CD4+CD25+T cell levels could reduce the incidence of GVHD.

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