Allogeneic Hematopoietic Stem Cell Transplantation Recipients Have Defects of Both Switched and IgM Memory B Cells

D’Orsogna, Lloyd; Wright, Matthew; Krueger, R.; McKinnon, E.; Buffery, Susan; Witt, Campbell S.; Staples, Nicole; Loh, Richard; Cannell, Paul; Christiansen, Frank; French, Martyn A.

doi:10.1016/j.bbmt.2008.11.024

Cited by 74 publications

(81 citation statements)

References 52 publications

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“…37 B-cell maturation after CBT remains suboptimal at 1-year post-transplant, as already described with other graft sources. 22 As B-cell maturation needs an interaction with CD4 þ T cells in germinal centers, the slow B-cell maturation after CBT may be explained at least in part by the length of CD4 þ maturation. Another explanation could be that B-cell maturation after CBT recapitulates B-cell maturation of the infant.…”

Section: Discussionmentioning

confidence: 99%

“…[14][15][16][17][18][19][20] Within the B cells, we explored the CD27 þ memory subset. [21][22][23] NK-cell maturation stages were explored by studying the CD56 bright , NKG2A þ and KIR þ cells. [24][25][26] Finally, we compared the recovery of cells involved in immune regulation, GVHD and GVL, by examining the proportion of invariant NKT (iNKT) cells within the CD3 population, [27][28][29] and CD25 þ FOXP3 þ T regulatory (Treg) cells within the CD4 þ compartment.…”

Section: Introductionmentioning

confidence: 99%

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Reconstitution of maturating and regulatory lymphocyte subsets after cord blood and BMT in children

Charrier

Cordeiro

Brito

et al. 2012

Bone Marrow Transplant

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Some clinical characteristics of cord blood transplantation (CBT) might be explained by specificities in the reconstitution of immune subsets differing by their maturation stage or their implication in GVHD, tolerance or immune responses against tumor or infectious agents. Here, we compare the immune reconstitution of several of these subsets after CBT and BMT. B-cell count recovery was faster after CBT. There was no difference in the recovery of CD4 þ and CD8 þ cell counts. There was no difference either in the frequency of several subsets: CD45RO þ memory, and CD45RA þ naïve cells within the CD4 þ T-cell compartment, CD27 þ among B cells, CD56 bright , NKG2A þ , and KIR þ cells among natural killer (NK) cells, CD25 þ FOXP3 þ regulatory T cells and invariant NKT cells. The proportion of the thymic naïve CD31 þ CD45RA þ CD4 þ T cells was lower after CBT at 6 months post-transplant, and was still below normal at 1 year in both groups. NK-cell expansion was more sustained after CBT, with fewer double-negative NKG2A À KIR À hyporesponsive cells and more double-positive NKG2A þ KIR þ hyper-responsive NK cells. These results, therefore, indicate that further research to improve CBT outcome should try to improve thymopoieisis and take advantage of the sustained NK-cell reconstitution. INTRODUCTIONAlmost all lethal complications of hematopoietic SCT, including leukemia relapse, and opportunistic infections, result from the post-transplant immune deficiency that lasts for months after transplantation. Therefore, the therapeutic challenge in improving the outcome for transplanted children outcome relies on the enhancement of immune reconstitution and the GVL effect, without increasing the harmful GVHD.Although lower rates of engraftment and GVHD and higher rates of life-threatening infections have been reported in patients who received cord blood transplantation (CBT), similar EFS and leukemia relapse rates have been observed after CBT and BMT. [1][2][3][4][5] These observations indicate that cord blood-derived immune cells have unique immune properties that allow for allogeneic tolerance while preserving the GVL effect.Previous studies have compared the reconstitution of the major immune cell populations after CBT and BMT: CD4 þ and CD8 þ T cells, natural killer (NK) and B cells. They showed that T-cell recovery is delayed, in particular CD8 þ T-lymphopoiesis after CBT, 2,6-9 although T-cell diversity has been shown to be similar in cord blood (CB) and BM recipients beyond 1 year after transplant. 7,10 Conversely, innate immunity recovery has been shown to be similar between CB and BM recipients, with normal cell counts of functional NK cells in the blood as soon as 1-month post-CBT. 2,11,12 Finally, B-cell number recovery appears to be faster after CBT. 6,9,13 Besides these differences in the reconstitution of the major lymphocyte populations, additional changes in the reconstitution of other immune cell subsets might occur and explain some of the clinical differences observed in patients who receive BMT or CBT.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reconstitution of maturating and regulatory lymphocyte subsets after cord blood and BMT in children

Charrier

Cordeiro

Brito

et al. 2012

Bone Marrow Transplant

View full text Add to dashboard Cite

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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.…”

Section: Introductionmentioning

confidence: 99%

“…12,13 Germinal-center (GC) defects contribute to the slow regeneration of isotype-class switched CD27 1 memory B cells, which correlates with long-term antibody class deficiencies in some patients. 8,9,[14][15][16] For CD27 2 immunoglobin D (IgD) 2 doublenegative (DN) B cells, reconstitution kinetics and function after allo-HSCT are completely unknown. 17,18 These B cells are assumed to be generated T-cell independently and might represent antigen-experienced cells at a time when GC reactions are defective.…”

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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“…6 Improved splenic function was accompanied by a concomitant restoration of the IgM memory B-cell pool. 15 cGvHD is also associated with a lack of IgM memory B cells 16,17 suggesting the presence of pitted red cells may be a surrogate marker for B-cell dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Functional hyposplenism after hematopoietic stem cell transplantation

Rozmus

Mallhi

et al. 2015

Bone Marrow Transplant

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Functional hyposplenism is associated with chronic GvHD (cGvHD) following hematopoietic stem cell transplantation (HSCT). We hypothesized that hyposplenism measured by pitted red cell counts in cGvHD was transient and related to the severity of disease. We performed a serial, retrospective review of 36 pediatric post-HSCT patients' pit counts at BC Children's Hospital from 2005 to 2013 and compared those counts with the clinical course of patients with late acute GvHD (aGvHD)/cGvHD. Of the 36 patients, 22 had late aGvHD/cGvHD based on National Institutes of Health consensus criteria. Fourteen of 22 GvHD patients had an abnormal pitted red cell count. Ten of 14 abnormal patients had late acute or overlap GvHD syndrome, primarily gastrointestinal disease. A second cohort was prospectively evaluated in a multicenter adult HSCT biomarker trial. We identified 3 out of 10 control patients who had an abnormal pitted red cell count, 3 out of 10 with classic cGvHD and 5 out of 9 patients with overlap syndrome were abnormal. In both the retrospective and prospective studies, hyposplenism was present in patients without late aGvHD/cGvHD suggesting current guidelines regarding antibiotic prophylaxis against encapsulated bacteria after HSCT need to be re-addressed and abnormal pit counts could be used to guide prophylaxis in all HSCT patients.

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Allogeneic Hematopoietic Stem Cell Transplantation Recipients Have Defects of Both Switched and IgM Memory B Cells

Cited by 74 publications

References 52 publications

Reconstitution of maturating and regulatory lymphocyte subsets after cord blood and BMT in children

Reconstitution of maturating and regulatory lymphocyte subsets after cord blood and BMT in children

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

Functional hyposplenism after hematopoietic stem cell transplantation

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