Immune Cell Subset Counts Associated with Graft-versus-Host Disease

Podgorny, Peter; Liu, Yiping; Dharmani‐Khan, Poonam; Pratt, Laura M.; Jamani, Kareem; Luider, Joanne; Auer-Grzesiak, Iwona; Mansoor, Adnan; Williamson, Tyler; Ugarte-Torres, Alejandra; Hoegh-Petersen, Mette; Stewart, Douglas A.; Daly, Andrew; Khan, Faisal; Russell, James A.; Storek, Jan

doi:10.1016/j.bbmt.2014.01.002

Cited by 47 publications

(58 citation statements)

References 67 publications

(71 reference statements)

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“…Chronic GvHD was, as expected, the second major event to shape long-term immune reconstitution. Chronic GvHD has already been reported to influence Band T-cell reconstitution 3,8,9,20,21,43,44 but none of these studies provided a broad overview as allowed here by CA. It is interesting to note that CMV-specific memory T cells cross react with alloantigens 45,46 and have long been suspected to be involved in the pathogenesis of GvHD through molecular mimicry.…”

Section: Discussionmentioning

confidence: 97%

“…2,3 Several studies have pinpointed the role of transplant characteristics, including conditioning regimen intensity, source of stem cells and donor matching, [4][5][6][7] and that of post-transplant events including acute (aGvHD) and chronic (cGvHD) graftversus-host disease and infections such as cytomegalovirus (CMV) replication on post-transplant immune reconstitution. [8][9][10] Other studies have focused on the study of a distinct subset of immune cells, e.g. regulatory T cells (Tregs), CD5 + B cells, or NK cells.…”

Section: Introductionmentioning

confidence: 99%

“…3 While molecular biology 8 and functional assays 14 can be used to study immune reconstitution, flow cytometry uniquely allows the simultaneous assessment of several immune populations. 9 Multivariate methods such as clustering algorithms, and principal component analyses are widely used to analyze multidimensional data such as gene expression profiles, but these methods have also been successfully applied to other types of data, such as clinical symptoms and murine hematopoietic reconstitution. 15,16 In the present study, we use these tools to analyze simultaneously the impact of several pre-and post-transplant variables on the immune reconstitution of a large number of immune cell populations.…”

Section: Introductionmentioning

confidence: 99%

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Cytomegalovirus shapes long-term immune reconstitution after allogeneic stem cell transplantation

et al. 2014

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Immune reconstitution after allogeneic stem cell transplantation is a dynamic and complex process depending on the recipient and donor characteristics, on the modalities of transplantation, and on the occurrence of graft-versushost disease. Multivariate methods widely used for gene expression profiling can simultaneously analyze the patterns of a great number of biological variables on a heterogeneous set of patients. Here we use these methods on flow cytometry assessment of up to 25 lymphocyte populations to analyze the global pattern of long-term immune reconstitution after transplantation. Immune patterns were most distinct from healthy controls at six months, and had not yet fully recovered as long as two years after transplant. The two principal determinants of variability were linked to the balance of B and CD8 + T cells and of natural killer and B cells, respectively. Recipient's cytomegalovirus serostatus, cytomegalovirus replication, and chronic graft-versus-host disease were the main factors shaping the immune pattern one year after transplant. We identified a complex signature of underand over-representation of immune populations dictated by recipient's cytomegalovirus seropositivity. Finally, we identified dimensions of variance in immune patterns as significant predictors of long-term non-relapse mortality, independently of chronic graft-versus-host disease.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cytomegalovirus shapes long-term immune reconstitution after allogeneic stem cell transplantation

et al. 2014

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“…Previous studies have demonstrated that phenotypic and functional recovery of donor T cells is often delayed for months to years after allogeneic HSCT. [1][2][3][4] Although most studies have focused on reconstitution of effector T cells, several studies have also examined recovery of CD4 regulatory T cells (CD4Tregs). [5][6][7][8][9] These studies suggest that CD4Treg deficiency can enhance alloreactivity and promote graftversus-host disease (GVHD).…”

Section: Introductionmentioning

confidence: 99%

Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD

Alho

Kim

Chammas

et al. 2016

Blood

148

137

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• Homeostatic recovery after allogeneic HSCT favors the production, expansion, and survival of effector T cells over CD4Tregs.• Unbalanced reconstitution of regulatory and effector T-cell subsets contributes to the development of chronic graftversus-host disease.The development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells. To characterize the complex mechanisms that lead to unbalanced recovery of these distinct T-cell populations, we studied 107 adult patients who received T-replete stem cell grafts after reduced-intensity conditioning. Immune reconstitution of CD4Treg, CD4Tcon, and CD8 T cells was monitored for a 2-year period. CD3 T-cell counts gradually recovered to normal levels during this period but CD8 T cells recovered more rapidly than either CD4Tregs or CD4Tcons. Reconstituting CD4Tregs and CD4Tcons were predominantly central memory (CM) and effector memory (EM) cells and CD8 T cells were predominantly terminal EM cells. Thymic generation of naive CD4Tcon and CD8 T cells was maintained but thymic production of CD4Tregs was markedly decreased with little recovery during the 2-year study. T-cell proliferation was skewed in favor of CM and EM CD4Tcon and CD8 T cells, especially 6 to 12 months after HSCT. Intracellular expression of BCL2 was increased in CD4Tcon and CD8 T cells in the first 3 to 6 months after HSCT. Early recovery of naive and CM fractions within each T-cell population 3 months after transplant was also strongly correlated with the subsequent development of chronic graft-versus-host disease (GVHD). These dynamic imbalances favor the production, expansion, and persistence of effector T cells over CD4Tregs and were associated with the development of chronic GVHD. (Blood. 2016;127(5):646-657)

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“…After allogeneic HSCT in humans, it is possible that aGVHD responses evolve as naïve T cells are activated by alloantigens and then proliferate and differentiate into memory subsets with effector functions. The recent observation in humans of increased numbers of CD4 þ and CD8 þ TEM cells at day þ28 after HSCT in patients who developed aGVHD suggests that TEMs play a role in aGVHD [27]. Interestingly, 2 early flow cytometric human studies that examined total CD4 þ and CD8 þ T cell populations in patients after allogeneic HSCT noted a predominant association of aGVHD with peripheral blood CD8 þ T cell populations or with decreasing CD4 to CD8 ratios, suggesting that CD8 þ T cell expansion plays an important role in human aGVHD [28,29].…”

Section: Introductionmentioning

confidence: 99%

Peripheral Blood CD38 Bright CD8+ Effector Memory T Cells Predict Acute Graft-versus-Host Disease

Khandelwal

Lane

Chaturvedi

et al. 2015

Biology of Blood and Marrow Transplantation

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Acute graft-versus-host disease (aGVHD) is mediated by allogeneic T cell responses. We hypothesized that increases of peripheral blood-activated CD8+ effector memory T (TEM) cells would be observed after hematopoietic stem cell transplantation (HSCT) before onset of aGVHD symptoms. Blood was collected twice weekly after HSCT for 7 weeks in 49 consecutive pediatric and adult HSCT recipients. Samples were incubated with fluorochrome-conjugated antibodies against CD45, CD3, CD8, CD38, CD45RA, and CCR7 and analyzed using flow cytometry. TEM cells were defined as CD3+ CD8+ CCR7- CD45RA(-) lymphocytes. CD38 expression was used as a marker of T cell activation. Patients were followed for 100 days for development of aGVHD. Twenty-three patients developed grade 1 to 4 aGVHD at a median of 37 days (range, 15 to 79 days) after HCST. Absolute CD38 bright CD8+ TEM of > 35 cells/μL predicted aGVHD at a median of 8 days (range, 1 to 34) before aGVHD onset with a sensitivity of 82.6% and specificity of 91.6%. The cumulative incidence of aGVHD was 90% in patients with absolute CD38 bright CD8+ TEM >35 cells/μL and 15% in patients without (P < .0001). Quantification of CD38 bright CD8+ TEM cells may predict aGVHD in children and young adult HSCT recipients.

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Immune Cell Subset Counts Associated with Graft-versus-Host Disease

Cited by 47 publications

References 67 publications

Cytomegalovirus shapes long-term immune reconstitution after allogeneic stem cell transplantation

Cytomegalovirus shapes long-term immune reconstitution after allogeneic stem cell transplantation

Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD

Peripheral Blood CD38 Bright CD8+ Effector Memory T Cells Predict Acute Graft-versus-Host Disease

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