Post-transplant evaluation of anti-HLA antibody in small bowel transplant recipients following T cell depletion protocols – case report

2005 ◽  
Vol 66 (8) ◽  
pp. 88
Author(s):  
M. Zahorchak ◽  
J. Howe ◽  
B. Hunter ◽  
L. Jelinek ◽  
A. Toth ◽  
...  
Keyword(s):  
Case Report ◽  
T Cell ◽  
Small Bowel ◽  
Cell Depletion ◽  
Transplant Recipients ◽  
T Cell Depletion ◽  
Post Transplant ◽  
Small Bowel Transplant ◽  
Transplant Evaluation ◽  
Hla Antibody

T-Cell Depletion and No Post-Transplant Immune Suppression Provides Better Immune Recovery to Aspergillus Than Conventional T Cell-Replete Hematopoietic Transplants.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2221-2221
Author(s):  
Katia Perruccio ◽  
Simone Cesaro ◽  
Fabiana Topini ◽  
Maria Vittoria Gazzola ◽  
Emanuela Burchielli ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Invasive Aspergillosis ◽  
Immune Suppression ◽  
Cell Depletion ◽  
Immune Recovery ◽  
Transplant Recipients ◽  
T Cell Depletion ◽  
Post Transplant ◽  
Cell Counts

Abstract After hematopoietic transplantation invasive aspergillosis is one of the most lethal infections. Susceptibility to invasive aspergillosis may be due to GvHD and its prophylaxis and treatment in T cell-replete transplants, and to T-cell-depletion in haploidentical transplants. Studies in mice and humans show that adaptive T-helper type-1 immune effector mechanisms are involved in control of invasive aspergillosis (Hebart et al. Blood, 2002; Cenci et al. J Immunol, 2000). In vivo T-cell priming induced by DCs pulsed with A. fumigatus conidia protects bone marrow transplanted mice from invasive aspergillosis (Bozza et al. Blood, 2000). This study monitored recovery of anti-Aspergillus immune competence in recipients of T cell-replete matched transplants and of T cell-depleted matched or haploidentical transplants for acute leukaemia. Patients: 32 pediatric recipients of matched T-replete transplants from unrelated donors (n=21), unrelated cord blood (n=2), and matched siblings (n=9) (median age: 10.5 years; range: 0.5–24); 20 adult recipients of matched T cell-depleted transplants (median age: 43 years; range 18–65), and 46 adult recipients of haploidentical transplants (median age: 34 years; range: 9–64). In all we monitored recovery of CD4+ T-cells and Aspergillus-specific CD4+ T-cells (by LDA) monthly for 18 months after transplant. Total CD4+ T-cell counts were higher after T-replete matched than after T-depleted matched or haploidentical transplant. At 9 months, CD4+ cells were: 1332±337 in T-cell replete transplant recipients, 364±62 in T cell-depleted matched transplant recipients, and 218±186 in haploidentical transplant recipients (p=0.000). Incidence of acute GvHD > grade II was 60% after T-replete transplantation, 0% after T cell-depleted matched and 9% after haploidentical transplantation. Aspergillus-specific T cells were first detected 15–18 months after T-replete matched transplantation (when immune suppressive GvHD prophylaxis/therapy was being withdrawn); 7–9 months after T cell-depleted matched transplantation and 9–12 months after haploidentical transplantation (p=0.000). Incidence of invasive aspergillosis was 21%, with a 10% mortality after T-replete transplants, 0% after T cell-depleted matched (p=0.000) and 7% with 4% mortality after haploidentical transplants (p=0.000). Although T cell counts were significantly higher after T-replete transplants their function appeared to be impaired by post-transplant immune suppression/GvHD. T-replete transplants were associated with a higher incidence of invasive aspergillosis and aspergillosis-related deaths. Specific Aspergillus immune competence recovered faster after T cell-depleted transplants, whether matched or haploidentical. These results show that T-cell depletion and no post-transplant immune suppression may provide a better pattern of immune recovery than T cell-replete transplantation and challenge the widely held belief that immune recovery after T cell-depleted transplants, particularly the haploidentical, is unduly delayed.

scholarly journals Impact of Different T Cell Depletion Protocols on Immune Reconstitution Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Amandine Pradier ◽  
Adrien Petitpas ◽  
Anne-Claire Mamez ◽  
Federica Giannotti ◽  
Sarah Morin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
The Impact

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic modality for a variety of hematological malignancies and congenital disorders. One of the major complications of the procedure is graft-versus-host-disease (GVHD) initiated by T cells co-administered with the graft. Removal of donor T cells from the graft is a widely employed and effective strategy to prevent GVHD, although its impact on post-transplant immune reconstitution might significantly affect anti-tumor and anti-infectious responses. Several approaches of T cell depletion (TCD) exist, including in vivo depletion using anti-thymocyte globulin (ATG) and/or post-transplant cyclophosphamide (PTCy) as well as in vitro manipulation of the graft. In this work, we analyzed the impact of different T cell depletion strategies on immune reconstitution after allogeneic HSCT. Methods We retrospectively analysed data from 168 patients transplanted between 2015 and 2019 at Geneva University Hospitals. In our center, several methods for TCD are being used, alone or in combination: 1) In vivo T cell depletion using ATG (ATG-Thymoglobulin 7.5 mg/kg or ATG-Fresenius 25 mg/kg); 2) in vitro partial T cell depletion (pTCD) of the graft obtained through in vitro incubation with alemtuzumab (Campath [Genzyme Corporation, Cambridge, MA]), washed before infusion and administered at day 0, followed on day +1 by an add-back of unmanipulated grafts containing about 100 × 106/kg donor T cells. The procedure is followed by donor lymphocyte infusions at incremental doses starting with 1 × 106 CD3/kg at 3 months to all patients who had received pTCD grafts with RIC in the absence of GVHD; 3) post-transplant cyclophosphamide (PTCy; 50 mg/kg) on days 3 and 4 post-HSCT. Absolute counts of CD3, CD4, CD8, CD19 and NK cells measured by flow cytometry during the first year after allogeneic HSCT were analyzed. Measures obtained from patients with mixed donor chimerism or after therapeutic DLI were excluded from the analysis. Cell numbers during time were compared using mixed-effects linear models depending on the TCD. Multivariable analysis was performed taking into account the impact of clinical factors differing between patients groups (patient's age, donor type and conditioning). Results ATG was administered to 77 (46%) patients, 15 (9%) patients received a pTCD graft and 26 (15%) patients received a combination of both ATG and pTCD graft. 24 (14%) patients were treated with PTCy and 26 (15%) patients received a T replete graft. 60% of patients had a reduced intensity conditioning (RIC). 48 (29%) patients received grafts from a sibling identical donor, 94 (56%) from a matched unrelated donor, 13 (8%) from mismatched unrelated donor and 13 (8%) received haploidentical grafts. TCD protocols had no significant impact on CD3 or CD8 T cell reconstitution during the first year post-HSCT (Figure 1). Conversely, CD4 T cells recovery was affected by the ATG/pTCD combination (coefficient ± SE: -67±28, p=0.019) when compared to the T cell replete group (Figure 1). Analysis of data censored for acute or chronic GVHD requiring treatment or relapse revealed a delay of CD4 T cell reconstitution in the ATG and/or pTCD treated groups on (ATG:-79±27, p=0.004; pTCD:-100±43, p=0.022; ATG/pTCD:-110±33, p<0.001). Interestingly, pTCD alone or in combination with ATG resulted in a better reconstitution of NK cells compared to T replete group (pTCD: 152±45, p<0.001; ATG/pTCD: 94±36, p=0.009; Figure 1). A similar effect of pTCD was also observed for B cells (pTCD: 170±48, p<.001; ATG/pTCD: 127±38, p<.001). The effect of pTCD on NK was confirmed when data were censored for GVHD and relapse (pTCD: 132±60, p=0.028; ATG/pTCD: 106±47, p=0.023) while only ATG/pTCD retained a significant impact on B cells (102±49, p=0.037). The use of PTCy did not affect T, NK or B cell reconstitution when compared to the T cell replete group. Conclusion Our results indicate that all TCD protocols with the only exception of PTCy are associated with a delayed recovery of CD4 T cells whereas pTCD of the graft, alone or in combination with ATG, significantly improves NK and B cell reconstitution. Figure 1 Disclosures No relevant conflicts of interest to declare.

T cell depletion and no post transplant immune suppression allow separation of graft versus leukemia from graft versus host disease

2019 ◽  
Vol 54 (S2) ◽  
pp. 775-779 ◽  
Author(s):  
Antonio Pierini ◽  
Loredana Ruggeri ◽  
Antonella Mancusi ◽  
Alessandra Carotti ◽  
Franca Falzetti ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
Immune Suppression ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Graft Versus Leukemia

A Comparative Analysis of Immune Reconstitution Following Reduced Intensity Conditioning with CAMPATH-1H and Total Lymphoid Irradiation/Anti-Thymocyte Globulin Prior to Allogeneic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1148-1148
Author(s):  
Brett Glotzbecker ◽  
Heidi Mills ◽  
Jacalyn Rosenblatt ◽  
Zekui Wu ◽  
Kerry Wellenstein ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Depletion ◽  
T Cell Proliferation ◽  
Reduced Intensity Conditioning ◽  
T Cell Depletion ◽  
Post Transplant ◽  
Initial Cohort ◽  
Reduced Intensity

Abstract Abstract 1148 Poster Board I-170 Graft versus host disease (GVHD) remains a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HCT). In vivo quantitative T-cell depletion using CAMPATH-1h (anti-CD52) has been explored in an effort to prevent acute GVHD. More recently, a regimen consisting of total lymphoid irradiation and anti-thymocyte globulin (ATG) has been shown to polarize T cells towards an inhibitory phenotype potentially reducing the associated risk for GVHD. However, these strategies may be associated with impaired post-transplant immune reconstitution, increased risk of tumor relapse and opportunistic infection. In this study we examined the pattern of cellular immune recovery following T cell depletion with CAMPATH-1h and compared results with an initial cohort of patients undergoing reduced intensity conditioning with TLI and ATG. Immunologic analyses were performed on twenty patients undergoing reduced intensity conditioning in conjunction with low dose CAMPATH -1h (50 mg) and an initial cohort of 5 patients treated with TLI/ATG. Conditioning with CAMPATH-1h resulted in the significant depletion of CD3, CD4, and CD8 T cells in the early post-transplant period and persistence of CD4 T cell depletion (< 200 cells /uL) for more than 6 months. Following TLI/ATG, persistent depletion of CD4+ T cells was also observed but no significant decrease in CD8 T cells was seen. A two-fold increase in circulating CD56+ NK cells, 21.8 to 41.6% (p=0.004), was seen following TLI-ATG, which was not noted following Campath conditioning. CAMPATH-1h conditioning was associated with a significant decrease in mean CD45RO+ memory T cells in the early post-transplant period (27.2 to 5.7% of the total population of nonadherent peripheral blood mononuclear cells, p=0.034). Relative percentages of naïve T cells (CD45RA+), central memory (CD45RO+CD62L+CCR7+) (CM), and effector memory (CD45RO+CD62L-CCR7-) (EM) T cells remained stable in the pre- and post-transplantation period. The CM:EM was 0.6 pre-transplant and at day 60, respectively. In contrast, T cell recovery in early post-transplant following the TLI/ATG regimen was associated with no reduction in CD45RO+ memory T cells. A significant rise in the relative percentages of naïve T cells from 39 to 61.3% (p=0.04), CM cells from 12 to 32.8% (p=0.05), a corresponding fall in EM cells from 57.9 to 32.5% (p=0.10), and a significant change in the CM:EM levels (0.2 pre-transplant, 1.0 day 60 post-transplant) was noted after TLI/ATG. The mean percentage of regulatory T cells as defined by the percentage of CD4+/CD25+ cells that express FoxP3 rose in the early post-transplant period following both regimens (8 to 20.7% at Day 30, p=0.003 in the CAMPATH group; 5.6 to 16.9% at Day 30, p=0.03 in the ATG/TLI group). Functional analyses demonstrated that the T cell proliferative response to the mitogen, Phytohemagglutinin (PHA), was profoundly depressed following CAMPATH-1h with mean SI decreasing from 34 pre-transplant to 1.4 at Day 30. In contrast, treatment with TLI/ATG resulted in no significant change in T cell proliferation in response to PHA with SI only decreasing from 45 pre-transplant to 36 at Day 30. Assessment of T cell polarization following stimulation with PHA or phorbol-ester (PMA)/ionomycin, recipient derived dendritic cells (DCs) or third party DCs demonstrated a rise of CD8+ T cells expressing, IL-4 and IL-10 consistent with a suppressor phenotype. Minimal T cell proliferation was observed following stimulation with patient derived DCs, which is consistent with suppression of the expansion of alloreactive T cells. In summary, both CAMPATH and TLI/ATG result in CD4+ T cell depletion but TLI/ATG resulted in relative preservation of CD8+ T cells, persistence of memory cells, relative preservation of central memory as compared to memory effector cells and intact response to mitogens. TLI/ATG therapy was also associated with the polarization of CD8+ T cells towards a Tc2 phenotype and lack of proliferation in response to recipient derived DCs. As such, TLI/ATG appears to be associated with more modest level of functional T cell depletion characterized by Tc2 polarization and suppression of host/donor alloreactivity. Disclosures Spitzer: Genzyme: Consultancy. Avigan:Genzyme: Consultancy.

Modulated Cyclophosphamide-Based In Vivo T-Cell Depletion Promotes Engraftment With Minimal Gvhd and Low Toxicity In Fanconi Anemia Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4561-4561
Author(s):  
Monica S Thakar ◽  
Mark C. Walters ◽  
Brenda M. Sandmaier ◽  
Rainer Storb ◽  
Mary E. D. Flowers ◽  
...  
Keyword(s):  
T Cell ◽  
Fanconi Anemia ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Old Patients ◽  
Post Transplant ◽  
Small Series

Building on a successful non-myeloablative conditioning regimen developed in Seattle (Blood 2003), Luznik and O´Donnell et al created a protocol that incorporates post-transplant cyclophosphamide (CY) after human leukocyte antigen (HLA)-haploidentical hematopoietic cell transplantation (HCT) (BBMT 2008). This method both promotes engraftment while selectively-depleting alloreactive donor T cells to prevent graft-versus-host disease (GVHD). We have previously shown that Fanconi Anemia (FA) patients can be treated with CY 60 mg/kg in a conditioning regimen with minimal toxicity (BBMT 2007), thus we adapted this post-HCT CY strategy for in vivo T-cell depletion in patients with FA. Between 2008 and 2012, four patients from three North American centers with FA and severe marrow failure in the absence of HLA-matched donors underwent HLA-haploidentical HCT. All four patients were referred for transplantation with minimal to no transfusion burden and all were in excellent clinical condition with HCT-CI scores of 0-2 and Lansky scores of 90-100%. Median age at transplant was 9.7 (6.9-11.9) years old. Patients were transplanted at a median of 1.6 (range, 0.6 -7.1) years after FA diagnosis. Conditioning consisted of fludarabine (150 mg/m2) and 2 Gy total body irradiation; one patient also received CY (10 mg/kg), which was deleted in subsequent patients to decrease the risk of mucositis. Marrow was infused on day 0, followed by post-grafting immunosuppression with CY (25 mg/kg/day, days +3, +4), mycophenolate mofetil, and cyclosporine, the latter two beginning at day +5 with plans to continue until days +35 and +180, respectively. Full donor engraftment was seen in all patients. Two patients developed acute grade I GVHD and none of the four patients has developed chronic extensive GVHD to date. With a follow-up of 5 years, 1 year, 11 months, and 9 months, all four patients are alive with stable, full donor chimerism, and are transfusion independent. While two patients required cyclosporine beyond day +180, only one patient currently remains on low-dose immunosuppression for treatment of limited chronic skin GVHD, which has now resolved. Our results confirm that modulated post-HCT CY can be used in patients with FA to promote engraftment across histocompatibility barriers. Despite concerns for both excessive toxicity related to CY and severe GVHD related to minimizing the dose of post-transplant CY, none of the FA patients in our small series experienced these problems. Our findings also suggest that transplant should not be delayed when there is lack of an HLA-matched donor. FA patients with few comorbidities and minimal transfusion burden can successfully undergo this HLA-haploidentical HCT approach. Disclosures: Off Label Use: MMF.

CIRCULATING DONOR-SPECIFIC ANTI-HLA ANTIBODY MAY IDENTIFY REJECTION-PRONE PEDIATRIC SMALL BOWEL TRANSPLANT RECIPIENTS

2010 ◽  
Vol 90 ◽  
pp. 403 ◽  
Author(s):  
C. Ashokkumar ◽  
A. Zeevi ◽  
C. Bentlejewski ◽  
J. Dobberstein ◽  
G. Mazariegos ◽  
...  
Keyword(s):  
Small Bowel ◽  
Transplant Recipients ◽  
Small Bowel Transplant ◽  
Hla Antibody

Post-Transplant Immune Suppressive Therapy Is Not Necessary In Related and Unrelated Reduced Intensity Conditioning Stem Cell Transplantation Using Low Dose Alemtuzumab In Vivo T Cell Depletion Combined with Alemtuzumab-Mediated In Vitro T Cell Depletion of the Graft

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2328-2328
Author(s):  
P.A. Von Dem Borne ◽  
C.J.M. Halkes ◽  
C.W.J. Starrenburg ◽  
W.A.F. Marijt ◽  
J.H.F. Falkenburg
Keyword(s):  
T Cell ◽  
Low Dose ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Suppressive Therapy ◽  
T Cell Depletion ◽  
Post Transplant ◽  
Immune Suppressive Therapy

Abstract Abstract 2328 Introduction T cell depletion with alemtuzumab administered in vivo to the patient reduces the risk of graft-versus-host disease (GVHD) and graft rejection following reduced intensity conditioning allogeneic stem cell transplantation (RIC SCT). However, high doses of alemtuzumab can result in delayed immune reconstitution, increased non relapse mortality (NRM) due to infections, and potential loss of graft versus tumor responses. Recently, the feasibility of T cell depletion with low dose in vivo alemtuzumab was demonstrated in HLA-identical related RIC SCT. Dose reduction of alemtuzumab to 30 mg combined with post-transplant immune suppressive therapy with cyclosporine tapered from 3 months after transplantation resulted in a low risk of GVHD, no increase in NRM and improved lymphocyte recovery (Chakraverty et al, Blood pre-published online June 29, 2010). Early immunotherapeutic intervention after SCT with donor lymphocytes may be hampered by the administration of post-transplant immune suppressive therapy. We investigated whether in RIC SCT using low dose in vivo alemtuzumab, post-transplant immune suppressive therapy can be replaced by alemtuzumab-mediated in vitro T cell depletion of the graft just prior to infusion (“Campath in the bag”). Patient and donor characteristics Between 2007 and 2009, 29 patients were transplanted with an unrelated donor, and 28 patients with a related donor using a RIC regimen consisting of fludarabine (50 mg/m2 p.o. day -10 to -5), busulphan (3.2 mg/kg i.v. day -6 and -5) and alemtuzumab (15 mg i.v. day -4 and -3), followed by infusion of the graft after in vitro incubation with 20 mg alemtuzumab. No additional immune suppressive therapy was used after SCT. Unrelated donors were matched for HLA-A, B, C, DR and DQ, three patient donor combinations had one HLA-DQ mismatch. Median patient age was 59 years (range 21–72). Remission status at the time of transplant was: 47% CR, 37% PR, 9% SD, 7% PD. Indications were diverse (19 AML, 16 myeloma, 6 CLL, 5 low grade NHL, 3 aggressive T-NHL, 2 aggressive B-NHL, 2 SAA, 1 CML, 1 myelofibrosis, 1 CMML, 1 ALL). The unrelated and related transplanted group were comparable regarding age, disease and remission status. The median Gratwohl transplantation risk score was 3 in the related group (range 1–5), and 5 in the unrelated group (range 3–6). Results All patients engrafted; platelet numbers of 50 × 109/L were reached after a median of 11 days (range 0–38 days), neutrophil numbers of 0.5 × 109/L were reached after a median of 18 days (range 0–161 days) post transplant. Two patients had secondary graft failure. In patients transplanted with a related donor, grade 1–2 and 3–4 acute GVHD was observed in 36% and 4% of evaluable patients, respectively, resolving in all patients without development of chronic GVHD. NRM was 0% at 3 months and 4% at 1 year. Overall survival was 100% at 3 months and 89% at 1 year. In patients transplanted with an unrelated donor more acute GVHD was observed (59% grade 1–2, 15% grade 3–4 of evaluable patients). 24% of evaluable patients developed chronic GVHD, which was limited in 75% and extensive in 25% of these patients. Chronic GVHD resolved in most patients, one patient has ongoing extensive chronic GVHD. NRM was 7% at 3 months and 24% at 1 year. Overall survival was 93% at 3 months and 55% at 1 year. Conclusions RIC SCT using low dose alemtuzumab in vivo T cell depletion combined with alemtuzumab-mediated in vitro T cell depletion of the graft without additional post-transplant immune suppressive therapy is feasible in patients transplanted with related and unrelated donors. Results are excellent in patients transplanted with related donors with low NRM and high overall survival. Although results are good in patients transplanted with unrelated donors considering the high Gratwohl score in this group, further improvement is being sought by increasing the efficiency of T cell depletion. This RIC SCT regimen without post-transplant immune suppressive therapy is an appropriate platform for early cellular immunotherapeutic interventions including donor lymphocyte infusion after SCT. Disclosures: No relevant conflicts of interest to declare.

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