A Comprehensive Comparison Immune Recovery In Adult Patients Following Allogeneic Umbilical Cord Blood, Matched Sibling and Matched Unrelated Donor Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2313-2313
Author(s):  
Lun-Wei Chiou ◽  
Junya Kanda ◽  
Paul Szabolcs ◽  
Gregory E. Sempowski ◽  
Jeffrey Hale ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Peripheral Blood ◽  
Nkt Cells ◽  
Unrelated Donor ◽  
Immune Recovery ◽  
Transplant Recipients ◽  
Cell Recovery ◽  
Matched Sibling

Abstract Abstract 2313 Immunologic reconstitution following stem cell transplantation (SCT) arises from thymic-independent peripheral expansion of memory T-cells transplanted with the stem cell graft, and thymic-dependent maturation of stem cell derived lymphoid progenitor cells. As a consequence of thymic involution, adult stem cell transplant recipients rely largely upon the thymic-independent pathway. This process is facilitated by a plentiful supply of mature T-cells contained within peripheral blood or bone marrow grafts. Umbilical cord blood (UCB) grafts contain predominantly naive T-cells thereby limiting the potential for thymic-independent immune recovery. Recent reports have documented slow immune recovery in adult UCB recipients, however it has yet to be described in the context of a comparable population of adult allogeneic matched sibling or unrelated donor SCT. Methods: Between 2007 and 2009, we characterized cellular immune reconstitution in a consecutive cohort of adult patients undergoing myeloablative SCT using either matched sibling (MSD), matched unrelated donor (MUD) peripheral blood stem cell (PBSC) or dual UCB donor grafts. Dual UCB transplant recipients were conditioned with TBI 1350cGy and fludarabine 160mg/m2 (Flu). PBSC recipients were conditioned with either TBI 1350cGy or IV busulfan 12.8mg/kg (Bu) and cyclophosphamide 120mg/kg, or Bu/Flu. PBSC grafts were allele-level matched at HLA-A, B, C and DRB1. UCB grafts were mismatched at no more than 2 class I or class II loci. Both cohorts received GvHD prophylaxis with Tacrolimus for at least 6 months. UCB recipients received mycophenolate mofetil 2g/day for at least 60 days instead of standard dose methotrexate GvHD prophylaxis for PBSC recipients. Quantification of the following lymphoid subsets were performed by flow cytometry on fresh peripheral blood prior to, and then at approximately 45, 100, 180, and 360 days following transplantation: NK and NKT cells, B-cells, plasmacytoid dendritic cells, CD3+, CD4+, CD8+, regulatory and na•ve T-cells. T-cell receptor excision circles (sjTREC) were quantified by real time PCR on DNA collected from an isolated fraction of CD3+ T-cells. Cumulative corticosteroid usage prior to day 100 (as determined by area under the curve) was determined as a method for comparing acute GvHD severity. The Kruskal-Wallis test with adjustments for multiple comparisons was used compare immune recovery values at 45, 100, 180 and 360 days post transplantation. The PearsonÕs Chi-square test was used to compare the CMV reactivation rate of UCB to MSD/MUD. Results: Forty-two recipients of allogeneic SCT (MSD-13, MUD-14, UCB-15) with successful donor engraftment and who survived a minimum of 6 months were evaluated. The MSD, MUD and UCB recipients had a median age of 41, 42 and 31 years, respectively (p = 0.13). There was no significant difference in corticosteroid administration before day 100 or chronic GvHD in the three cohorts (p=0.74). There were no differences in the kinetics of immune recovery between MSD and MUD recipients. At 45 days following transplantation, UCB recipients had significantly lower levels of CD4+ (figure), CD8+ and NKT-cells. By day 100, UCB recipients had similar numbers of CD4+ T-cells, but remained lower in the other major T-cell subsets. By day 180 however, all T-cell subsets except NKT cells (p=0.033) were similar to the MSD/MUD recipients. NK cell recovery was faster in the UCB recipients (figure). There was also no difference in B-cell recovery among the 3 cohorts. TREC levels were not significantly different in recipients of all graft types, but were uniformly low (figure). The slow recovery of T-cells in the UCB cohort corresponds with a higher Kaplan-Meier estimate of CMV reactivation compared to the MSD/MUD cohort (90% vs. 36%; p = 0.0078). Conclusion: Compared to HLA-identical MSD and MUD adult SCT recipients, quantitative lymphoid recovery in UCB transplant recipients is slower in the first two months, but these differences are erased by 4–6 months following transplantation. NK reconstitution is more rapid in UCB recipients. Reduction of early opportunistic infections affecting UCB transplant recipients may arise from effective techniques to boost early T-cell recovery. Disclosures: No relevant conflicts of interest to declare.

scholarly journals T Cell-Depleted Related Haploidentical Peripheral Blood Stem Cell Transplantation in a Patient with Fanconi Anemia. Cagliari Experience.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5175-5175
Author(s):  
Maria Adele Sanna ◽  
Maria Grazia Orofino ◽  
Fausto Cossu ◽  
Maria Carmen Addari ◽  
Antonio Piroddi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
Bone Marrow Failure ◽  
Unrelated Donor ◽  
Cd34 Cells

Abstract Stem cell transplantation is presently the best treatment for Fanconi Anaemia (FA) patients developing bone marrow failure. 70% of success is reported in patients with a HLA identical sibling whereas the outcome for HSCT in those transplanted from unrelated donors is in the range of 29–43%, graft rejection, GVHD and regimen related toxicity beeing the main causes of failure. This results limited the ability to perform marrow transplantation other than HLA identical siblings for this disease. Recently a fludarabine based cytoreductive regimen has been successfully used in T cell depleted haploidentical/mismatched transplant of FA patients. We report a case of a 7 year old boy with bone marrow failure since 1999. Androgens treatment was uneffective, no HLA identical family donor was available and the search for a suitable marrow or cord blood unrelated donor was unsuccessful. After 4 years he underwent T-cell depleted haploidentical PBSCT from his father. Conditioning regimen was: fludarabine 30 mg/mq from day −6 to day −3, cytoxan 300 mg/mq from day −6 to day −3, rabbit ATG (3.75 mg/kg) from day −5 to day −3. GvHD prophylaxis consisted of cyclosporine 1 mg/kg from day −1. The donor received G-CSF 8 ug/kg/dose twice daily for 6 days and underwent leukapheresis on day 5 and 6. Donor stem cells were depleted of T cells by positive selection of CD34+ cells using the Clinimacs device according to the suggested procedures (Milteny Biotec). On day 0, 15.3x106 x kg CD34+ cells were infused with 1.5 x 105 CD3 + cells. The clinical postransplant course was uneventful. Neutrophil engraftment ( >0.5 x 109 ) occurred on day 14, platelet count >100x109 on day 15. He was discharged on day 39 without signs of GVHD. Molecular analysis of DNA-VNTRs at 1, 3, 6, 9, 12 months showed >95% donor chimerism on peripheral blood. At 14 months after transplantation the patient is well, normal blood cell count (WBC 5.4 x 109/l, Hb 13.6 gr /dl, platelets 293x 109 /l). Count of T-cells are reported in the normal reference range ( CD3+ :1865 ug/l, CD8+ :1026ug/l, CD19+ :732ug/l, CD56+: 452). Karnofsky score is 100%. Conclusion: the case reported shows that the fludarabine based regimen and the infusion of a high number of T-cell depleted CD34+ was successful in absence of peri-transplant complications and can be proposed for the cure of FA patients at high risk of clonal disease and without HLA-matched sibling donor.

scholarly journals Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation

Blood ◽  
2012 ◽  
Vol 120 (24) ◽  
pp. 4882-4891 ◽  
Author(s):  
Miguel-Angel Perales ◽  
Jenna D. Goldberg ◽  
Jianda Yuan ◽  
Guenther Koehne ◽  
Lauren Lechner ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Phase 1 ◽  
Effector Memory ◽  
Immune Recovery ◽  
Cell Recovery ◽  
Hematopoietic Stem

Abstract Delays in immune recovery after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection and relapse. IL-7 has a central role in T-cell development and survival and enhances immune recovery in murine models of allo-HSCT. We performed a phase 1 trial of r-hIL-7 (CYT107) in recipients of T-cell depleted allo-HSCTs. Twelve patients were treated with escalating doses of r-hIL-7 administered weekly for 3 weeks. The study drug was well tolerated with only one patient developing acute skin GVHD. At baseline, patients were profoundly lymphopenic. CYT107 induced a doubling in CD4+ and CD8+ T cells. The main effect of IL-7 was an expansion of effector memory T cells, the predominant subset identified in our patients. There was no significant effect on CD4+CD25+FoxP3+ T cells, NK, or B cells. Importantly, we not only saw quantitative increases in T cells after a short course of IL-7 but also demonstrated an increase in functional T cells, including viral-specific T cells that recognize CMV. Enhanced TCR diversity was also observed after treatment. Our results indicate that r-hIL-7 can enhance immune recovery after a T cell–depleted allo-HSCT without causing significant GVHD or other serious toxicity (www.clinicaltrials.gov; NCT00684008).

Phenotypic and Functional Analysis of T-Cells Mobilized in HLA-Matched Sibling Donors Following Treatment with the Chemokine Antagonist AMD3100.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3001-3001 ◽  
Author(s):  
Michael Rettig ◽  
Steven M. Devine ◽  
Julie Ritchey ◽  
John F. DiPersio
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Phenotypic Properties ◽  
Functional Changes ◽  
Cd8 Cells ◽  
Matched Sibling

Abstract We are currently evaluating a novel method for the procurement of peripheral blood stem cells from HLA matched sibling donors using a direct antagonist of the CXCR4/SDF-1 interaction called AMD3100 (A). Donors receive a single subcutaneous injection of A and then undergo a 20 liter leukapheresis (LP) four hours later. The LP product is then cryopreserved and subsequently transplanted following ablative conditioning. To date, we have performed 15 transplants with allografts collected following A alone. In comparison to allografts collected following five days of G-CSF, A mobilized allografts contain approximately 50% less CD34+ cells but 2–3 times more CD3+ cells. Nevertheless, the kinetics of neutrophil and platelet engraftment have been virtually identical to that observed following G-mobilized allografts and grades 2–4 acute GVHD has been observed in only 20% of recipients. We sought to analyze the functional and phenotypic properties of T cells collected following A alone to understand the relatively low rates of acute GVHD despite the transplantation of higher T-cell doses. In 3 donors, extensive T cell phenotyping was performed on donor peripheral blood prior to A, 6 hours following A, and also on the LP product collected after A. Specifically, we were seeking to determine whether any alteration in CD4+ or CD8+ subsets had occurred. We analyzed T-cell subsets using well described markers for central memory, effector memory, naïve, and effector memory RA phenotypes. We also assessed expression of CD62L, CD127, CCR7, and SLAM family members (CD48, CD150, and CD244) on both CD4+ and CD8+ cells. The activation status on CD4 and CD8 cells was assessed using markers for CD25, CD30, and CD69. Finally we assessed for quantitative changes in the mobilization of regulatory T cells by assaying the proportion of CD4+CD25+FoxP3+ cells mobilized following A. In none of these analyses could we detect any significant alteration in the relative ratios of CD4 or CD8 subsets mobilized by A. Finally, the functional capacity of purified CD3+ cells collected following A was assessed using a NOD/SCID xenogeneic GVHD model we have recently developed. In that model, survival of mice transplanted with A mobilized T-cells was similar to that observed with untreated T cells, suggesting that A mobilized T cells retain their GVHD-inducing capacity. In summary, these preliminary data suggest that AMD3100 induces a “pan-mobilization” of T cell subsets without any apparent skewing toward a particular subset. These studies are in contrast to others suggesting subtle phenotypic and functional changes in donor T cells after mobilization with G-CSF. Further studies evaluating A mobilized allografts are ongoing.

Functional Comparison and Longitudinal Assessment of Tri-Functional T-Cells Recognizing CMV pp65 and IE-1 Polypeptides in Hematopoietic Stem Cell and Solid Organ Transplant Recipients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2936-2936
Author(s):  
Don J. Diamond ◽  
Simon F. Lacey ◽  
Corinna La Rosa ◽  
Wendy Zhou ◽  
Ghislaine Gallez-Hawkins ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Hematopoietic Stem ◽  
Specific Ctls ◽  
Tnf Α ◽  
Ifn Γ ◽  
Cmv Disease

Abstract Reconstitution of adaptive T-cell responses to human cytomegalovirus (CMV) is critical to protection from CMV disease following hematopoietic stem cell (HSCT) or solid organ transplantation (SOT). However, there is an incomplete understanding of which CMV antigens and epitopes are most crucial to providing protective responses. The functional status of cytotoxic T-lymphocyte (CTL) populations recognizing cytomegalovirus IE-1 and pp65 polypeptides was investigated in PBMC from either HSCT or SOT recipients. Our previous finding of differing levels of degranulation between CMV IE1 and pp65/pp50 specific T-cells was complicated by the possibility that differences were epitope and/or HLA-specific. We generalized the approach using a combined flow-based CD107a/b degranulation/mobilization and intracellular cytokine (ICC) assays using peptide libraries as antigens. These assays indicated that a significantly higher proportion of pp65-specific CTLs were in a more mature functional state compared to IE-1-specific CTLs. Degranulation/multicytokine ICC assays also indicated that a significantly higher proportion of the pp65-specific versus IE-1-specific CTLs secreted both IFN-γ and TNF-α, in addition to possessing greater cytotoxic potential. These results support our earlier findings of functional differences between CTLs recognizing individual epitopes within the IE-1 and pp65 antigens in HSCT recipients, and extend them to a broader array of HLA-restricted responses to those antigens. A report that a subset of HIV-1 specific CTLs capable of producing both IFN-γ and TNF-α was associated with improved cytotoxic activity prompted us to investigate whether degranulation, a functional correlate of cytotoxicity, was positively associated with dual cytokine production and predicted differences between IE1 and pp65-specific CD8+ T-cells. A higher proportion of pp65-specific compared to IE1-specific T-cells were present in the trifunctional IFN-γ+,TNF-α+, CD107+ population (p=0.008) in HSCT recipients. We have extended these findings to investigate the role of donor CMV status in terms of functional maturity of CMV-specific T cell response in transplant recipients. T cell maturation/function may act as a mechanistic correlate to the survival advantage of recipients receiving a stem-cell graft from CMV sero-positive donors. These principles have also been applied to investigations of a high risk population of sero-negative recipients of a sero-positive liver allograft. Data from this study will also be reviewed in the context of the model of trifunctional T cells being indicative of enhanced protective capacity against CMV disease and associated with survival.

Early Recovery of Thymus-Derived Naïve T Cells in Pediatric Patients (pts) Treated with Non-Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation (NMSCT) for Cancer.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 310-310
Author(s):  
Terry J. Fry ◽  
Alison R. Rager ◽  
Frances Hakim ◽  
Cynthia Love ◽  
Paula Layton ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Risk ◽  
Peripheral Blood ◽  
T Cell Subsets ◽  
Immune Recovery ◽  
Early Recovery ◽  
Thymic Function ◽  
Cell Counts ◽  
Increased Risk

Abstract Background: Current SCT approaches consistently achieve rapid donor myeloid engraftment, but delayed immune recovery remains a significant obstacle and results in increased risk of infection and relapse. T cells are regenerated via 2 pathways, thymus-derived and peripheral expansion, processes for which IL-7 is critical. We postulated that non-myeloablative pre-transplant conditioning might preserve thymic function in pediatric SCT recipients thus enhancing thymus-derived naïve T cell regeneration. Methods: We analyzed T cell subsets, T cell receptor excision circles (TREC), and IL-7 levels in peripheral blood after SCT in 21 pediatric pts with high-risk malignancies (median age 14, range 4–21). Fludarabine-based induction chemotherapy was administered for disease control and targeted CD4 count reduction. Pre-transplant conditioning consisted of cyclophosphamide (1,200 mg/m2/day) and fludarabine (30 mg/m2/day) × 4 days plus melphalan (100 mg/m2 × 1 dose in sarcoma pts). Grafts consisted of G-CSF mobilized unmodified peripheral blood stem cells from 5–6/6 HLA-matched first-degree relatives (median CD34 dose 11.7 × 10E6/kg, range 4.4–19.1; median CD3 dose 416 × 10E6/kg, range 228–815). Cyclosporine was used for GVHD prophylaxis. Results: Donor-derived engraftment was rapid (absolute neutrophil count > 500/uL median day 9, range 8–11). Complete donor lymphoid chimerism (>95% by VNTR-PCR on CD3 sorted peripheral blood) was achieved in all by day 28. Immune recovery was brisk and sustained. Substantial numbers of naïve (CD45RA+/CD62L+) CD4+ and CD8+ T-cells were detected at day 28 (Fig 1). There was a steady increase in TREC from 3 to 12 months consistent with early, robust thymic-dependant T cell generation (Fig 2). This was not seen in adult pts treated on a parallel trial (data not shown). IL-7 levels were elevated and inversely correlated with T cell counts (r=−0.56, p<0.0001). Conclusions: Targeted immune depletion and NMSCT results in rapid, sustained immune reconstitution in pediatric pts with malignancy. Preserved thymic function appears to contribute to naïve T cell recovery in this setting. We postulate that non-myeloablative conditioning is thymus sparing and that this, in combination with immune depletion-induced IL-7 elevation, promotes early thymic-derived lymphoid recovery. This approach may serve as a strategy to overcome the prolonged immunodeficiency commonly encountered after allogeneic SCT in pediatrics and might be used as a platform to direct allogeneic anti-tumor immune responses in high-risk childhood cancers. Figure 1 Figure 1. Figure 2 Figure 2.

Immune Reconstitution In Anti-Thymocyte Globulin Conditioned Unrelated Donor Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2071-2071 ◽  
Author(s):  
David Jared Kobulnicky ◽  
Roy T Sabo ◽  
Allison F Scalora ◽  
David Portier ◽  
Devon Fletcher ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Unrelated Donor ◽  
Cell Recovery ◽  
Ebv Reactivation ◽  
Stem Cell Source ◽  
Cell Source

Abstract Anti-thymocyte globulin (ATG) is widely used for in vivo T cell depletion and immunomodulation in unrelated donor (URD) stem cell transplantation (SCT) to reduce the risk of graft vs. host disease (GVHD). However, despite the reduction in GVHD risk, outcomes are generally not superior to matched related donor (MRD) SCT conditioned without ATG. This is primarily because of defective immune reconstitution and high rates of opportunistic infections in ATG recipients. We have previously reported equivalent outcomes in URD SCT recipients conditioned with ATG when compared to MRD recipients. We now report immune reconstitution in an expanded cohort of these patients. Patients with AML, ALL, MDS, MPD (n=142) transplanted between 2004 and 2011 were included in this retrospective review. Seventy eight received either bone marrow or peripheral blood stem cell (PBSC) grafts from URD and received either 10 or 7.5 mg/kg rabbit ATG (Thymoglobulin, Sanofi-Aventis) during conditioning, those with MRD did not. Conditioning was myeloablative in all patients. Lymphoid recovery was equivalent in the two cohorts during the first year following SCT except in the first month (Figure), when URD recipients had lower absolute lymphocyte count (μ-URD=0.6x103/ μ L, μ-MRD=1.1; repeated measures mixed model p=0.022). Age, CD3/34 cell dose infused, stem cell source and conditioning intensity were not associated with ALC recovery post transplant. In a subset of patients lymphocyte subset enumeration was performed following withdrawal of immunosuppression, at an average 237 days post-SCT. ATG recipients had significantly lower mean CD4+ counts (μ-URD=267 (n=30), μ-MRD =434/ μ L (n=27); ANCOVA p = 0.003), however no significant differences were observed in CD3+, CD8+, CD19+ or CD56+ cell recovery. ATG recipients were significantly more likely to have complete donor T cell chimerism at 1 (OR = 12.5, CI= 2.4, 66.0, p = 0.001) and 2 months post-SCT (OR = 6.5 , CI=1.5, 27.4, p = 0.013), however by 9 months following SCT this trend had reversed with a greater likelihood of mixed T cell chimerism (OR > 100; p = 0.017), suggesting re-emergence of recipient derived T cell clones. Consequently, donor lymphocyte infusions were given significantly more often to ATG recipients (12/78) than to non-recipients (2/64) (OR = 5.64, CI = 1.21, 26.20, p=0.027). High grade CMV viremia (1000 copies/ μL) was significantly more likely in CMV sero-positive ATG recipients (n=18/55) than in non-recipients (n=7/48) (OR = 2.8, CI 1.1, 7.6, p = 0.032). Reduced intensity conditioning and PBSC were associated with higher CMV reactivation in ATG recipients and there was a lower likelihood of survival in these individuals than in those who did not receive ATG (HR: 0.53, CI: 0.31, 0.92; p = 0.024). EBV reactivation was observed more often in susceptible ATG recipients (n=22/58) than in non-recipients (n=5/43), (OR=4.6, CI=1.6, 13.6, p= 0.003). The median peak EBV viral load in ATG recipients (u=1545 copies/ μL, IQR: 288, 2,302) was significantly higher than in non-recipients (u=120 IQR: 57, 169, p = 0.005). PBSC stem cell source (p = 0.049) and HLA mismatch (p =< 0.001) were associated with EBV reactivation in ATG recipients but not in non-recipients. ATG recipients were also more likely to experience a fungal infection (OR=2.8, CI=1.1, 6.7, p=0.023). 1-month ALC was predictive of disease free survival whereby it had a significant negative effect on relapse (HR = 0.33; 95% CI: 0.16, 0.66; p = 0.002). As 1-month ALC increased by one-tenth, the odds of relapse decreased by over 3% and survival increased by 3%. In conclusion, high doses of ATG used during conditioning are associated with an early retardation of lymphoid recovery post-SCT, and with late mixed T cell chimerism accompanied by a delay in CD4+ T cell recovery. This is associated with a higher rate of viral reactivation in PBSC recipients and of fungal infections in general. Lower doses of ATG should be used in SCT and in ATG conditioned SCT, early intervention with DLI, particularly CD8+ cell depleted DLI as reported by others, may help restore T cell repertoire and improve SCT outcomes and survival. Disclosures: Toor: Sanofi Avnetis: Research Funding.

Favorable Immune Reconstitution Profile after Allogeneic Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2236-2236
Author(s):  
Omer Hassan Jamy ◽  
Ayman Saad ◽  
Rachael Orlandella ◽  
Samantha B Langford ◽  
Ravi K. Paluri ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Research Funding ◽  
Immune Reconstitution ◽  
First Year ◽  
Gvhd Prophylaxis ◽  
One Year

Abstract Background: The administration of post-transplant high-dose cyclophosphamide (PTCy) has been shown to be an effective strategy for GvHD prophylaxis following allogeneic peripheral blood stem cell transplantation(PBSCT) from alternative donors. PTCy is toxic to allogeneic activated proliferating T lymphocytes, such as effector T cells. Conversely, it may not materially affect memory T cells. Methods: We evaluated immune reconstitution profile and transplant outcome in patients who received PBSCT with and without PTCy. PTCy was given on day +3 and +4 following haploidentical transplant (HAPLO), or only on day +3 following HLA-matched unrelated donor (MUD) transplant. No PTCy was given to patients with HLA-matched related donors (MRD). All patients received GvHD prophylaxis as tacrolimus (day +5 to +180) and MMF (day +5 to +35). Preparative regimens were myeloablative regimens (fludarabine/busulfan, fludarabine/TBI 12 Gy, or CY/TBI 12) in all patients except 4 patients (received fludarabine/melphalan). Immune reconstitution profile (IRP) was tested via serial flow cytometry analysis of peripheral blood lymphocytes after transplant were done on days +30, +100, and +180. Results: Data of 70 patients who underwent allogeneic PBSCT in our institution were analyzed in 3 groups; MRD (n=22), MUD (n=35), and HAPLO (n=13). The total cohort had 33 males (47%), and had median age of 52 years (range 20-70). All patients had hematological malignancy except one patient with HLH. The median duration of follow up was 6 months (range 1-17). The median day of neutrophil and platelet engraftment were 13, 12, 17 and 18, 15, 22 days for MRD, MUD and HAPLO groups respectively. The one-year overall survival of the whole group was 67% (95% confidence interval: 48-80) with no difference in OS among the 3 cohorts (log rank P value 0.4) (Figure 1). Lymphocyte and lymphocyte subset (T, B, NK) count recovery for MUD and HAPLO was significantly less (p<0.05) than MRD during the first month post-HSCT but these differences were statistically insignificant by day +60 and remained so through day +365. Recovery of both CD4+ and CD8+ naïve T cell (CD45RA+CD27+CD197+) population was generally slower for HAPLO patients during the first year and significantly less through day+ 180 for CD4+ T cells. As predicted, central memory (CD45RA-CD27+CD197+) CD4+ and CD8+ T cells remained proportionately equivalent at 40% and 28% respectively for all groups during the first year. The effector memory (CD45RA-CD27+CD197-) population was also proportionately consistent at 25% of total for both CD4+ and CD8+ subsets. Interestingly, the effector T cell population (CD45RA+CD27-CD197-) trended higher for all three recipient groups at each time point for both CD4+ and CD8+ populations increasing from 20% at one month to over 40% at one year. Conclusion: Post-PBSCT survival was not significantly different from alternative donor graft recipients and those that received MRD PBSCT. Lymphocyte recovery was impaired for the PTCy groups in the immediate post-PBSCT period but quickly recovered to that seen in MRD recipients. Figure 1 Figure 1. Disclosures Saad: Spectrum: Honoraria; American Porphyria foundation: Research Funding; Astellas: Research Funding; Alexion: Honoraria. Lamb:Incysus, Ltd: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Rapid reconstitution of Epstein-Barr virus–specific T lymphocytes following allogeneic stem cell transplantation

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2814-2821 ◽  
Author(s):  
Natalie A. Marshall ◽  
John Greg Howe ◽  
Richard Formica ◽  
Diane Krause ◽  
John E. Wagner ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Hla Class I ◽  
Barr Virus ◽  
Matched Sibling ◽  
Epstein Barr

Epstein-Barr virus (EBV)–specific CD8 T lymphocytes are present at remarkably high frequencies in healthy EBV+individuals and provide protection from EBV-associated lymphoproliferative diseases. Allogeneic peripheral blood stem cell transplantation (allo-PBSCT) is a commonly used therapy in which T-cell surveillance for EBV is temporarily disrupted. Herein, human leukocyte antigen (HLA) class I tetramers were used to investigate the reestablishment of the EBV-specific CD8 T-cell repertoire in patients following allo-PBSCT. CD8+ T cells specific for lytic and latent cycle–derived EBV peptides rapidly repopulate the periphery of matched sibling allo-PBSCT patients. The relative frequencies of T cells specific for different EBV peptides in transplantation recipients closely reflect those of their respective donors. Investigation of patients at monthly intervals following unmanipulated allo-PBSCT demonstrated that the frequency of EBV-specific T cells correlates with the number of EBV genome copies in the peripheral blood and that expansion of EBV-specific T-cell populations occurs even in the setting of immunosuppressive therapy. In contrast, patients undergoing T-cell–depleted or unrelated cord blood transplantation have undetectable EBV-specific T cells, even in the presence of Epstein-Barr viremia. The protective shield provided by EBV-specific CD8 T cells is rapidly established following unmanipulated matched sibling allo-PBSCT and demonstrates that HLA class I tetramers complexed with viral peptides can provide direct and rapid assessment of pathogen-specific immunity in this and other vulnerable patient populations.

Sign in / Sign up

Export Citation Format

Share Document