Pretransplant chemotherapy reduces inflammatory cytokine production and acute graft-versus-host disease after allogeneic bone marrow transplantation

Geoffrey R. Hill, Kenneth R Cooke, Yani S. Brinson, David Bungard, James L M Ferrara

Research output: Contribution to journalArticle

Abstract

Background. Tumor necrosis factor-α (TNF-α) is known to be a critical effector molecule in the pathogenesis of graft-versus-host disease (GVHD), and elevated levels during bone marrow transplantation (BMT) conditioning are associated with more severe GVHD. Many patients receive chemotherapy prior to BMT, but its effect on subsequent toxicities is controversial. Methods. We studied the effect of prior chemotherapy on GVHD severity and inflammatory cytokine generation in a well-established murine model of allogeneic BMT (B6 → B6D2F1). Results. Three weeks after a single dose of cyclophosphamide, bone marrow and splenic cellularity was reduced by 50% and the production of TNF-α to LPS stimulation by macrophages was also markedly impaired (both before and after total body irradiation). Allogeneic BMT recipients previously treated with cyclophosphamide had significantly less GVHD and improved survived relative to recipients previously pretreated with diluent only. This survival advantage was associated with reduced systemic levels of both TNF-α and interleukin-1β 7 days after BMT. This reduction occurred despite equivalent serum levels of lipopolysaccharide, consistent with the reductions in TNF-α and interleukin-1β production by host macrophages after cyclophosphamide pretreatment. Conclusions. These data support the notion that patients entering BMT conditioning without prior cytotoxic treatment (e.g., patients with chronic myeloid leukemia) may be at increased risk of posttransplant complications associated with excessive inflammatory cytokine production.

Original languageEnglish (US)
Pages (from-to)1478-1480
Number of pages3
JournalTransplantation
Volume67
Issue number11
DOIs
StatePublished - Jun 15 1999
Externally publishedYes

Fingerprint

Homologous Transplantation
Graft vs Host Disease
Bone Marrow Transplantation
Cytokines
Drug Therapy
Transplantation Conditioning
Tumor Necrosis Factor-alpha
Cyclophosphamide
Interleukin-1
Macrophages
Interleukin-7
Whole-Body Irradiation
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lipopolysaccharides
Bone Marrow
Survival
Serum

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Pretransplant chemotherapy reduces inflammatory cytokine production and acute graft-versus-host disease after allogeneic bone marrow transplantation. / Hill, Geoffrey R.; Cooke, Kenneth R; Brinson, Yani S.; Bungard, David; Ferrara, James L M.

In: Transplantation, Vol. 67, No. 11, 15.06.1999, p. 1478-1480.

Research output: Contribution to journalArticle

Hill, Geoffrey R. ; Cooke, Kenneth R ; Brinson, Yani S. ; Bungard, David ; Ferrara, James L M. / Pretransplant chemotherapy reduces inflammatory cytokine production and acute graft-versus-host disease after allogeneic bone marrow transplantation. In: Transplantation. 1999 ; Vol. 67, No. 11. pp. 1478-1480.
@article{62fc9ac54ae0474bb8e4815ae1b90ec7,
title = "Pretransplant chemotherapy reduces inflammatory cytokine production and acute graft-versus-host disease after allogeneic bone marrow transplantation",
abstract = "Background. Tumor necrosis factor-α (TNF-α) is known to be a critical effector molecule in the pathogenesis of graft-versus-host disease (GVHD), and elevated levels during bone marrow transplantation (BMT) conditioning are associated with more severe GVHD. Many patients receive chemotherapy prior to BMT, but its effect on subsequent toxicities is controversial. Methods. We studied the effect of prior chemotherapy on GVHD severity and inflammatory cytokine generation in a well-established murine model of allogeneic BMT (B6 → B6D2F1). Results. Three weeks after a single dose of cyclophosphamide, bone marrow and splenic cellularity was reduced by 50{\%} and the production of TNF-α to LPS stimulation by macrophages was also markedly impaired (both before and after total body irradiation). Allogeneic BMT recipients previously treated with cyclophosphamide had significantly less GVHD and improved survived relative to recipients previously pretreated with diluent only. This survival advantage was associated with reduced systemic levels of both TNF-α and interleukin-1β 7 days after BMT. This reduction occurred despite equivalent serum levels of lipopolysaccharide, consistent with the reductions in TNF-α and interleukin-1β production by host macrophages after cyclophosphamide pretreatment. Conclusions. These data support the notion that patients entering BMT conditioning without prior cytotoxic treatment (e.g., patients with chronic myeloid leukemia) may be at increased risk of posttransplant complications associated with excessive inflammatory cytokine production.",
author = "Hill, {Geoffrey R.} and Cooke, {Kenneth R} and Brinson, {Yani S.} and David Bungard and Ferrara, {James L M}",
year = "1999",
month = "6",
day = "15",
doi = "10.1097/00007890-199906150-00015",
language = "English (US)",
volume = "67",
pages = "1478--1480",
journal = "Transplantation",
issn = "0041-1337",
publisher = "Lippincott Williams and Wilkins",
number = "11",

}

TY - JOUR

T1 - Pretransplant chemotherapy reduces inflammatory cytokine production and acute graft-versus-host disease after allogeneic bone marrow transplantation

AU - Hill, Geoffrey R.

AU - Cooke, Kenneth R

AU - Brinson, Yani S.

AU - Bungard, David

AU - Ferrara, James L M

PY - 1999/6/15

Y1 - 1999/6/15

N2 - Background. Tumor necrosis factor-α (TNF-α) is known to be a critical effector molecule in the pathogenesis of graft-versus-host disease (GVHD), and elevated levels during bone marrow transplantation (BMT) conditioning are associated with more severe GVHD. Many patients receive chemotherapy prior to BMT, but its effect on subsequent toxicities is controversial. Methods. We studied the effect of prior chemotherapy on GVHD severity and inflammatory cytokine generation in a well-established murine model of allogeneic BMT (B6 → B6D2F1). Results. Three weeks after a single dose of cyclophosphamide, bone marrow and splenic cellularity was reduced by 50% and the production of TNF-α to LPS stimulation by macrophages was also markedly impaired (both before and after total body irradiation). Allogeneic BMT recipients previously treated with cyclophosphamide had significantly less GVHD and improved survived relative to recipients previously pretreated with diluent only. This survival advantage was associated with reduced systemic levels of both TNF-α and interleukin-1β 7 days after BMT. This reduction occurred despite equivalent serum levels of lipopolysaccharide, consistent with the reductions in TNF-α and interleukin-1β production by host macrophages after cyclophosphamide pretreatment. Conclusions. These data support the notion that patients entering BMT conditioning without prior cytotoxic treatment (e.g., patients with chronic myeloid leukemia) may be at increased risk of posttransplant complications associated with excessive inflammatory cytokine production.

AB - Background. Tumor necrosis factor-α (TNF-α) is known to be a critical effector molecule in the pathogenesis of graft-versus-host disease (GVHD), and elevated levels during bone marrow transplantation (BMT) conditioning are associated with more severe GVHD. Many patients receive chemotherapy prior to BMT, but its effect on subsequent toxicities is controversial. Methods. We studied the effect of prior chemotherapy on GVHD severity and inflammatory cytokine generation in a well-established murine model of allogeneic BMT (B6 → B6D2F1). Results. Three weeks after a single dose of cyclophosphamide, bone marrow and splenic cellularity was reduced by 50% and the production of TNF-α to LPS stimulation by macrophages was also markedly impaired (both before and after total body irradiation). Allogeneic BMT recipients previously treated with cyclophosphamide had significantly less GVHD and improved survived relative to recipients previously pretreated with diluent only. This survival advantage was associated with reduced systemic levels of both TNF-α and interleukin-1β 7 days after BMT. This reduction occurred despite equivalent serum levels of lipopolysaccharide, consistent with the reductions in TNF-α and interleukin-1β production by host macrophages after cyclophosphamide pretreatment. Conclusions. These data support the notion that patients entering BMT conditioning without prior cytotoxic treatment (e.g., patients with chronic myeloid leukemia) may be at increased risk of posttransplant complications associated with excessive inflammatory cytokine production.

UR - http://www.scopus.com/inward/record.url?scp=0033564477&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033564477&partnerID=8YFLogxK

U2 - 10.1097/00007890-199906150-00015

DO - 10.1097/00007890-199906150-00015

M3 - Article

C2 - 10385089

AN - SCOPUS:0033564477

VL - 67

SP - 1478

EP - 1480

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 11

ER -