Loss of T Follicular Helper Cells in the Peripheral Blood of Patients with Chronic Graft-versus-Host Disease

David A. Knorr; Hongbo Wang; Mukta Aurora; Margaret L MacMillan; Shernan G Holtan; Rachel Bergerson; Qing Cao; Daniel J Weisdorf; Sarah A Cooley; Claudio G Brunstein; Jeffrey S Miller; John E Wagner; Bruce R Blazar; Michael R Verneris

doi:10.1016/j.bbmt.2016.01.003

Loss of T Follicular Helper Cells in the Peripheral Blood of Patients with Chronic Graft-versus-Host Disease

David A. Knorr, Hongbo Wang, Mukta Aurora, Margaret L MacMillan, Shernan G Holtan, Rachel Bergerson, Qing Cao, Daniel J Weisdorf, Sarah A Cooley, Claudio G Brunstein, Jeffrey S Miller, John E Wagner, Bruce R Blazar, Michael R Verneris

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Abstract

B cell antihost antibody production plays a central role in chronic graft-versus-host disease (cGVHD). T follicular helper (TFH) cells drive B cell responses and are implicated in this process. Given differences in cGVHD incidence between umbilical cord blood (UCB) and adult donor transplant recipients, we evaluated TFH cell reconstitution kinetics to define graft source differences and their potential pathogenic role in cGVHD. Although we observed significantly fewer TFH cells in the blood of UCB recipients (versus matched related donors [MRD]) early after transplantation, by 1 year the numbers of TFH cells were similar. Additionally, at both early (day 60) and late (1 year) time points, TFH cell phenotype was predominantly central memory cells in both cohorts. TFH cells were functional and able to produce multiple cytokines (INF-γ, TNF-α, IL-2, IL-17, and IL-21) after stimulation. In contrast to mouse models, where an enhanced frequency of splenic TFH cells contributes to cGVHD, patients with cGVHD showed significantly depleted circulating TFH cells after both UCB and MRD transplantation. Low numbers of TFH cells early after UCB transplantation could directly contribute to less cGVHD in this cohort. Additionally, systemic therapy (including steroids and calcineurin inhibitors) may contribute to decreases in TFH cells in patients with cGVHD. These data provide further evidence supporting the importance of TFH cells in cGVHD pathogenesis.

Original language	English (US)
Pages (from-to)	825-833
Number of pages	9
Journal	Biology of Blood and Marrow Transplantation
Volume	22
Issue number	5
DOIs	https://doi.org/10.1016/j.bbmt.2016.01.003
State	Published - May 1 2016

Bibliographical note

Funding Information:
Research reported in this publication was supported by the NIH MSTP Grant T32 GM008244 (D.A.K.) and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114 (D.A.K., M.R.V., J.S.M., and B.R.B.). This work was also supported by NIH R01 AI100879 (M.R.V. and J.S.M.), 5R01AI100879 (M.R.V., D.J.W., S.C., and J.S.M.), P01 CA142106 (B.R.B.), and P01 CA065493-21 (M.R.V., S.C., J.S.M., B.R.B., and J.E.W.).

Publisher Copyright:
© 2016.

Keywords

Chronic graft-versus-host disease
T follicular helper cells
Umbilical cord blood

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10.1016/j.bbmt.2016.01.003

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Knorr, D. A., Wang, H., Aurora, M., MacMillan, M. L., Holtan, S. G., Bergerson, R., Cao, Q., Weisdorf, D. J., Cooley, S. A., Brunstein, C. G., Miller, J. S., Wagner, J. E., Blazar, B. R., & Verneris, M. R. (2016). Loss of T Follicular Helper Cells in the Peripheral Blood of Patients with Chronic Graft-versus-Host Disease. Biology of Blood and Marrow Transplantation, 22(5), 825-833. https://doi.org/10.1016/j.bbmt.2016.01.003

Knorr, DA, Wang, H, Aurora, M, MacMillan, ML , Holtan, SG, Bergerson, R, Cao, Q , Weisdorf, DJ, Cooley, SA, Brunstein, CG, Miller, JS , Wagner, JE , Blazar, BR & Verneris, MR 2016, 'Loss of T Follicular Helper Cells in the Peripheral Blood of Patients with Chronic Graft-versus-Host Disease', Biology of Blood and Marrow Transplantation, vol. 22, no. 5, pp. 825-833. https://doi.org/10.1016/j.bbmt.2016.01.003

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title = "Loss of T Follicular Helper Cells in the Peripheral Blood of Patients with Chronic Graft-versus-Host Disease",

abstract = "B cell antihost antibody production plays a central role in chronic graft-versus-host disease (cGVHD). T follicular helper (TFH) cells drive B cell responses and are implicated in this process. Given differences in cGVHD incidence between umbilical cord blood (UCB) and adult donor transplant recipients, we evaluated TFH cell reconstitution kinetics to define graft source differences and their potential pathogenic role in cGVHD. Although we observed significantly fewer TFH cells in the blood of UCB recipients (versus matched related donors [MRD]) early after transplantation, by 1 year the numbers of TFH cells were similar. Additionally, at both early (day 60) and late (1 year) time points, TFH cell phenotype was predominantly central memory cells in both cohorts. TFH cells were functional and able to produce multiple cytokines (INF-γ, TNF-α, IL-2, IL-17, and IL-21) after stimulation. In contrast to mouse models, where an enhanced frequency of splenic TFH cells contributes to cGVHD, patients with cGVHD showed significantly depleted circulating TFH cells after both UCB and MRD transplantation. Low numbers of TFH cells early after UCB transplantation could directly contribute to less cGVHD in this cohort. Additionally, systemic therapy (including steroids and calcineurin inhibitors) may contribute to decreases in TFH cells in patients with cGVHD. These data provide further evidence supporting the importance of TFH cells in cGVHD pathogenesis.",

keywords = "Chronic graft-versus-host disease, T follicular helper cells, Umbilical cord blood",

author = "Knorr, {David A.} and Hongbo Wang and Mukta Aurora and MacMillan, {Margaret L} and Holtan, {Shernan G} and Rachel Bergerson and Qing Cao and Weisdorf, {Daniel J} and Cooley, {Sarah A} and Brunstein, {Claudio G} and Miller, {Jeffrey S} and Wagner, {John E} and Blazar, {Bruce R} and Verneris, {Michael R}",

note = "Funding Information: Research reported in this publication was supported by the NIH MSTP Grant T32 GM008244 (D.A.K.) and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114 (D.A.K., M.R.V., J.S.M., and B.R.B.). This work was also supported by NIH R01 AI100879 (M.R.V. and J.S.M.), 5R01AI100879 (M.R.V., D.J.W., S.C., and J.S.M.), P01 CA142106 (B.R.B.), and P01 CA065493-21 (M.R.V., S.C., J.S.M., B.R.B., and J.E.W.). Publisher Copyright: {\textcopyright} 2016.",

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AU - Knorr, David A.

AU - Wang, Hongbo

AU - Aurora, Mukta

AU - MacMillan, Margaret L

AU - Holtan, Shernan G

AU - Bergerson, Rachel

AU - Cao, Qing

AU - Weisdorf, Daniel J

AU - Cooley, Sarah A

AU - Brunstein, Claudio G

AU - Miller, Jeffrey S

AU - Wagner, John E

AU - Blazar, Bruce R

AU - Verneris, Michael R

N1 - Funding Information: Research reported in this publication was supported by the NIH MSTP Grant T32 GM008244 (D.A.K.) and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114 (D.A.K., M.R.V., J.S.M., and B.R.B.). This work was also supported by NIH R01 AI100879 (M.R.V. and J.S.M.), 5R01AI100879 (M.R.V., D.J.W., S.C., and J.S.M.), P01 CA142106 (B.R.B.), and P01 CA065493-21 (M.R.V., S.C., J.S.M., B.R.B., and J.E.W.). Publisher Copyright: © 2016.

PY - 2016/5/1

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N2 - B cell antihost antibody production plays a central role in chronic graft-versus-host disease (cGVHD). T follicular helper (TFH) cells drive B cell responses and are implicated in this process. Given differences in cGVHD incidence between umbilical cord blood (UCB) and adult donor transplant recipients, we evaluated TFH cell reconstitution kinetics to define graft source differences and their potential pathogenic role in cGVHD. Although we observed significantly fewer TFH cells in the blood of UCB recipients (versus matched related donors [MRD]) early after transplantation, by 1 year the numbers of TFH cells were similar. Additionally, at both early (day 60) and late (1 year) time points, TFH cell phenotype was predominantly central memory cells in both cohorts. TFH cells were functional and able to produce multiple cytokines (INF-γ, TNF-α, IL-2, IL-17, and IL-21) after stimulation. In contrast to mouse models, where an enhanced frequency of splenic TFH cells contributes to cGVHD, patients with cGVHD showed significantly depleted circulating TFH cells after both UCB and MRD transplantation. Low numbers of TFH cells early after UCB transplantation could directly contribute to less cGVHD in this cohort. Additionally, systemic therapy (including steroids and calcineurin inhibitors) may contribute to decreases in TFH cells in patients with cGVHD. These data provide further evidence supporting the importance of TFH cells in cGVHD pathogenesis.

AB - B cell antihost antibody production plays a central role in chronic graft-versus-host disease (cGVHD). T follicular helper (TFH) cells drive B cell responses and are implicated in this process. Given differences in cGVHD incidence between umbilical cord blood (UCB) and adult donor transplant recipients, we evaluated TFH cell reconstitution kinetics to define graft source differences and their potential pathogenic role in cGVHD. Although we observed significantly fewer TFH cells in the blood of UCB recipients (versus matched related donors [MRD]) early after transplantation, by 1 year the numbers of TFH cells were similar. Additionally, at both early (day 60) and late (1 year) time points, TFH cell phenotype was predominantly central memory cells in both cohorts. TFH cells were functional and able to produce multiple cytokines (INF-γ, TNF-α, IL-2, IL-17, and IL-21) after stimulation. In contrast to mouse models, where an enhanced frequency of splenic TFH cells contributes to cGVHD, patients with cGVHD showed significantly depleted circulating TFH cells after both UCB and MRD transplantation. Low numbers of TFH cells early after UCB transplantation could directly contribute to less cGVHD in this cohort. Additionally, systemic therapy (including steroids and calcineurin inhibitors) may contribute to decreases in TFH cells in patients with cGVHD. These data provide further evidence supporting the importance of TFH cells in cGVHD pathogenesis.

KW - Chronic graft-versus-host disease

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Loss of T Follicular Helper Cells in the Peripheral Blood of Patients with Chronic Graft-versus-Host Disease

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