Immune reconstitution after hematopoietic cell transplantation

Bosch, Mark; Khan, Faisal; Storek, Jan

doi:10.1097/moh.0b013e328353bc7d

Cited by 187 publications

(188 citation statements)

References 164 publications

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“…Studies in both mouse and man have indicated that the lymphopenic state is associated with a spectrum of T cell abnormalities, including spontaneous proliferation, conversion to activated/memory phenotype, and tissue infiltration and damage (1)(2)(3)(4). In addition, spontaneous proliferation is usually oligoclonal, leading to constriction of the T cell repertoire (5)(6)(7)(8). Development of protocols that allow full reconstitution of the peripheral T cell compartment without inflammatory sequelae is an important aspect of ensuring good outcomes after lymphopenia-inducing therapeutic regimens.…”

Section: Introductionmentioning

confidence: 99%

Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease

Bolton¹,

Zhu²,

Terry³

et al. 2015

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 99%

Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease

Bolton¹,

Zhu²,

Terry³

et al. 2015

Journal of Clinical Investigation

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“…9 In the first months, immune competence is in part restored in a thymus-independent fashion by proliferation of the T cells in response to increased levels of homeostatic cytokines or exogenous antigens. 1,10 Production of new T cells occurs only later by resumed thymic output. 10 The unmanipulated graft contains subsets of naive and memory T cells with defined specificities that display distinct proliferative and persistence capacities in response to lymphopenia.…”

Section: Introductionmentioning

confidence: 99%

“…Immunosuppressants are, unfortunately, not selective for alloreactive T cells and may thus limit adaptive immune responses to opportunistic infections and cancer. 1 Depletion of T cells from the allograft prevents GVHD but results in delayed reconstitution and increased morbidity and mortality due to opportunistic infections and tumor relapse. 2 High-dose cyclophosphamide given early posttransplant (pt-Cy) has been proposed to selectively spare bystander naive and memory T cells while depleting alloreactive T cells in vivo after infusion of unmanipulated grafts.…”

Section: Introductionmentioning

confidence: 99%

Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation

Roberto

Castagna

Zanon

et al. 2015

Blood

133

149

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Key Points• T SCM are abundant early after allogeneic hematopoietic stem cell transplantation and derive from naive T cells that survived pt-Cy.• Pt-Cy allows the generation of donor primary and recall responses in transplanted patients, even in the presence of persistent antigen.Early T-cell reconstitution following allogeneic transplantation depends on the persistence and function of T cells that are adoptively transferred with the graft. Posttransplant cyclophosphamide (pt-Cy) effectively prevents alloreactive responses from unmanipulated grafts, but its effect on subsequent immune reconstitution remains undetermined.Here, we show that T memory stem cells (T SCM ), which demonstrated superior reconstitution capacity in preclinical models, are the most abundant circulating T-cell population in the early days following haploidentical transplantation combined with pt-Cy and precede the expansion of effector cells. Transferred naive, but not T SCM or conventional memory cells preferentially survive cyclophosphamide, thus suggesting that posttransplant T SCM originate from naive precursors. Moreover, donor naive T cells specific for exogenous and self/tumor antigens persist in the host and contribute to peripheral reconstitution by differentiating into effectors. Similarly, pathogen-specific memory T cells generate detectable recall responses, but only in the presence of the cognate antigen. We thus define the cellular basis of T-cell reconstitution following pt-Cy at the antigen-specific level and propose to explore naive-derived T SCM in the clinical setting to overcome immunodeficiency. These trials were registered at www.clinicaltrials.gov as #NCT02049424 and #NCT02049580. (Blood. 2015;125(18):2855-2864

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“…[7][8][9] Low B-cell counts and immunosuppression cause weak vaccination responses within the first year after transplantation. 2 Immunoglobulin quantification as a measurement of self-acquired B-cell immunity is complicated by immunoglobulin substitution and blood product transfer containing residual amounts of plasma. ELISpot analysis could be a more precise method to determine B-cell capacity to differentiate into antibody-secreting cells after in vitro stimulation and thus to estimate B-cell immunity after transplant.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow T-cell infiltration during acute GVHD is associated with delayed B-cell recovery and function after HSCT

Mensen

Jöhrens

Anagnostopoulos

et al. 2014

Blood

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Key Points• Donor T-cell infiltration of the bone marrow is associated with impaired B-cell immunity after allogeneic HSCT.• Quantification of k-deleting recombination excision circles as a biomarker for bone marrow B-cell output in different clinical episodes.B-cell immune dysfunction contributes to the risk of severe infections after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Delayed B-cell regeneration is found in patients with systemic graft-versus-host disease (GVHD) and is often accompanied by bone marrow (BM) suppression. Little is known about human BM GVHD. We analyzed the reconstitution kinetics of B-cell subsets in adult leukemic patients within 6 months after allo-HSCT. B-cell deficiency already existed before transplant and was aggravated after transplant. Onset of B-cell reconstitution characterized by transitional B-cell recovery occurred either early (months 2-3) or late (from month 6 on) and correlated highly positively with reverse transcription-polymerase chain reaction quantified numbers of k-deleting recombination excision circles (KRECs). Delayed recovery was associated with systemic acute GVHD and full-intensity conditioning therapy. Histological analysis of BM trephines revealed increased T-cell infiltration in late recovering patients, which was associated with reduced numbers of osteoblasts. Functionally, late recovering patients displayed less pneumococcal polysaccharide-specific immunoglobin M-producing B cells on ex vivo B-cell activation than early recovering patients. Our results provide evidence for acute BM GVHD in allo-HSCT patients with infiltrating donor T cells and osteoblast destruction. This is associated with delayed B-cell reconstitution and impaired antibody response. Herein, KREC appears suitable to monitor BM B-cell output after transplant. (Blood. 2014;124(6):963-972)

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Immune reconstitution after hematopoietic cell transplantation

Abstract: Lessons learned from observational studies on immune reconstitution are leading to new strategies to prevent or treat posttransplant infections. Additional knowledge is needed to develop effective strategies to prevent or treat relapse, second malignancies and GVHD.

Cited by 187 publications

References 164 publications

Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease

Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease

Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation

Bone marrow T-cell infiltration during acute GVHD is associated with delayed B-cell recovery and function after HSCT

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