γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes

Airoldi, Irma; Bertaina, Alice; Prigione, Ignazia; Zorzoli, Alessia; Pagliara, Daria; Cocco, Claudia; Meazza, Raffaella; Loiacono, Fabrizio; Lucarelli, Barbarella; Bernardo, Maria Ester; Barbarito, Giulia; Pende, Daniela; Moretta, Alessandro; Pistoia, Vito; Moretta, Lorenzo; Locatelli, Franco

doi:10.1182/blood-2014-09-599423

Cited by 218 publications

(235 citation statements)

References 59 publications

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“…Notably, together with high numbers of CD34 + HSC, this graft contains donor-derived, mature NK cells and γδ T cells 20 which may confer prompt protection against both leukemia recurrence and infections. 21 As recently shown, NK cell reconstitution after HSCT can be highly accelerated by human cytomegalovirus (HCMV) infection/reactivation. 22,23 Indeed, in patients receiving umbilical cord blood transplantation (UCBT), HCMV infection induced a rapid development of mature NK cells characterized by the KIR +…”

Section: Analysis Of Memory-like Natural Killer Cells In Human Cytomementioning

confidence: 99%

Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing +T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies

Muccio¹,

Bertaina

Falco

et al. 2015

Haematologica

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W e analyzed the impact of human cytomegalovirus infection on the development of natural killer cells in 27 pediatric patients affected by hematological malignancies, who had received a HLA-haploidentical hematopoietic stem cell transplantation, depleted of both α/β+ T cells and B cells. In line with previous studies in adult recipients of umbilical cord blood transplantation, we found that human cytomegalovirus reactivation accelerated the emergence of mature natural killer cells. Thus, most children displayed a progressive expansion of a memory-like natural killer cell subset expressing NKG2C, a putative receptor for human cytomegalovirus, and CD57, a marker of terminal natural killer cell differentiation. NKG2C + CD57+ natural killer cells were detectable by month 3 following hematopoietic stem cell transplantation and expanded until at least month 12. These cells were characterized by high killer Ig-like receptors (KIRs) and leukocyte inhibitory receptor 1 (LIR-1) and low Siglec-7, NKG2A and Interleukin-18Rα expression, killed tumor targets and responded to cells expressing HLA-E (a NKG2C ligand). In addition, they were poor Interferon-γ producers in response to Interleukin-12 and Interleukin-18. The impaired response to these cytokines, together with their highly differentiated profile, may reflect their skewing toward an adaptive condition specialized in controlling human cytomegalovirus. In conclusion, in pediatric patients receiving a type of allograft different from umbilical cord blood transplantation, human cytomegalovirus also induced memory-like natural killer cells, possibly contributing to controlling infections and reinforcing anti-leukemia effects.

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Section: Analysis Of Memory-like Natural Killer Cells In Human Cytomementioning

confidence: 99%

Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing +T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies

Muccio¹,

Bertaina

Falco

et al. 2015

Haematologica

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“…6,[10][11][12][13][14][15] There have been several reports on HHCT in pediatric patients. 4,5,7,[16][17][18] In our current study, all 42 patients achieved stable engraftment early post transplant at a median of 10 days. No patient experienced graft failure (GF), including late GF.…”

Section: Discussionmentioning

confidence: 95%

“…[1][2][3] Moreover, preliminary reports on the new method of αβ + T-cell depletion showed further improved outcomes for T-cell-depleted haploidentical transplants. 4,5 Depletion of αβ + T cells produces grafts containing many γδ + lymphocytes and other effector cells. While αβ + T cells are known to be associated with the initiation of GvHD, γδ + T cells can enhance immune reconstitution and are not implicated in GvHD.…”

Section: Introductionmentioning

confidence: 99%

Haploidentical HCT using an αβ T-cell-depleted graft with targeted αβ+ cells by add-back after a reduced intensity preparative regimen containing low-dose TBI

Koh

et al. 2016

Bone Marrow Transplant

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Between 2012 and 2015, 42 pediatric patients underwent haploidentical hematopoietic cell transplantation using an αβ + T-cell-depleted graft with targeted αβ cells at 1-5 × 10 5 /kg by add-back; 31 had hematologic malignancy (HM), 8 had non-malignant disease (NM) and 3 had solid tumors. All patients received uniform reduced-intensity conditioning with fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin and low-dose TBI. All 42 patients achieved neutrophil engraftment at a median of 10 days. The cumulative incidences (CIs) of ⩾ grade II and ⩾ grade III acute GvHD were 31 ± 7.1% (SE) and 12 ± 5.0%, respectively, and 1-year CI of chronic GvHD was 15 ± 5.8%. One patient died of CMV pneumonia, leading to transplant-related mortality (TRM) of 2.6 ± 2.5%. Sixteen patients relapsed and 11 died of disease. At a median follow-up of 19 months (range, 5-43 months), the estimated 2-year event-free survival for NM and HM were 88 ± 11.7 and 50 ± 10.1%, respectively. Our study demonstrated that haploidentical hematopoietic cell transplantation after ex vivo depletion of αβ + T cells with targeted dose noticeably reduced the graft failure rate and TRM in pediatric patients and could be applied to patients lacking a suitable related or unrelated donor. While αβ + T cells are known to be associated with the initiation of GvHD, γδ + T cells can enhance immune reconstitution and are not implicated in GvHD. 6 Recently, we reported our experience with HHCT using a CD3-depleted graft. 7 Since 2012, we have initiated HHCT using ex vivo depletion of αβ + T cells with targeted αβ cells at 1-5 × 10 5 /kg after add-back. Here, we report our prospective results using αβ-depleted grafts in HHCT for children and adolescents with malignant or non-malignant disease.

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“…[88] Attempts to improve immune reconstitution and graft-versus-tumor effect after T-cell depleted alloHSCT recently led to the development of a new method of T-cell depletion based on the specific elimination of mature T cells carrying α and β chains of the TCR (αβ + T cells) and preservation of donorderived NK cells and TCRγδ + T cells in the graft. [89] This approach was recently reported to efficiently prevent aGVHD after HLA-haploidentical alloHSCT, without any need for posttransplant pharmacologic prophylaxis [81] (Table 1).…”

Section: Depletion Of T-cell Subtype(s)mentioning

confidence: 99%

Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Servais

Béguin

Delens

et al. 2016

Expert Opinion on Investigational Drugs

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Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) offers potential curative treatment for a wide range of malignant and nonmalignant hematological disorders. However, its success may be limited by post-transplant acute graft-versus-host disease (aGVHD), a systemic syndrome in which donor's immune cells attack healthy tissues in the immunocompromised host. aGVHD is one of the main causes of morbidity and mortality after alloHSCT. Despite standard GVHD prophylaxis regimens, aGVHD still develops in approximately 40-60% of alloHSCT recipients. Areas covered: In this review, after a brief summary of current knowledge on the pathogenesis of aGVHD, the authors review the current combination of a calcineurin inhibitor with an antimetabolite with or without added anti-thymocyte globulin (ATG) and emerging strategies for GVHD prevention. Expert opinion: A new understanding of the involvement of cytokines, intracellular signaling pathways, epigenetics and immunoregulatory cells in GVHD pathogenesis will lead to new standards for aGVHD prophylaxis allowing better prevention of severe aGVHD without affecting graft-versus-tumor effects.ARTICLE HISTORY

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γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes

Abstract: Key Points Vδ1 and Vδ2 T cells promptly reconstitute in children given haploidentical stem cell transplantation depleted of αβ+ T and CD19+ B cells. Vδ1 cells are expanded in patients experiencing cytomegalovirus reactivation; ZOL potentiates Vδ2 killing against leukemia blasts.

Cited by 218 publications

References 59 publications

Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing +T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies

Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing +T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies

Haploidentical HCT using an αβ T-cell-depleted graft with targeted αβ+ cells by add-back after a reduced intensity preparative regimen containing low-dose TBI

Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

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