Postgrafting administration of granulocyte colony-stimulating factor impairs functional immune recovery in recipients of human leukocyte antigen haplotype-mismatched hematopoietic transplants.
In human leukocyte antigen haplotype-mismatched transplantation, extensive T-cell depletion prevents graft-versus-host disease (GVHD) but delays immune recovery. Granulocyte colony-stimulating factor (G-CSF) is given to donors to mobilize stem cells and to recipients to ensure engraftment. Studies have shown that G-CSF promotes T-helper (Th)-2 immune deviation which, unlike Th1 responses, does not protect against intracellular pathogens and fungi. The effect of administration of G-CSF to recipients of mismatched hematopoietic transplants with respect to transplantation outcome and functional immune recovery was investigated. In 43 patients with acute leukemia who received G-CSF after transplantation, the engraftment rate was 95%. However, the patients had a long-lasting type 2 immune reactivity, ie, Th2-inducing dendritic cells not producing interleukin 12 (IL-12) and high frequencies of IL-4- and IL-10-producing CD4(+) cells not expressing the IL-12 receptor beta(2) chain. Similar immune reactivity patterns were observed on exposure of donor cells to G-CSF. Elimination of postgrafting administration of G-CSF in a subsequent series of 36 patients with acute leukemia, while not adversely affecting engraftment rate (93%), resulted in the anticipated appearance of IL-12-producing dendritic cells (1-3 months after transplantation versus > 12 months in transplant recipients given G-CSF), of CD4(+) cells of a mixed Th0/Th1 phenotype, and of antifungal T-cell reactivity in vitro. Moreover, CD4(+) cell counts increased in significantly less time. Finally, elimination of G-CSF-mediated immune suppression did not significantly increase the incidence of GVHD (< 15%). Thus, this study found that administration of G-CSF to recipients of T-cell-depleted hematopoietic transplants was associated with abnormal antigen-presenting cell functions and T-cell reactivity. Elimination of postgrafting administration of G-CSF prevented immune dysregulation and accelerated functional immune recovery.
Volpi
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I
Division of Hematology and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Perugia, Italy.
Perruccio
K
K
Tosti
A
A
Capanni
M
M
Ruggeri
L
L
Posati
S
S
Aversa
F
F
Tabilio
A
A
Romani
L
L
Martelli
M F
MF
Velardi
A
A
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D001230:Aspergillus / Q000276:immunology; D018791:CD4 Lymphocyte Count; D002175:Candida / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000276:immunology; D004198:Disease Susceptibility; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000453:epidemiology; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects*; D006239:Haplotypes; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000139:chemically induced*; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007938:Leukemia / Q000276:immunology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D021122:Protein Subunits; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D016879:Salvage Therapy; D018418:Th2 Cells / Q000276:immunology; D016896:Treatment Outcome
D021122:Protein Subunits; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor; D018664:Interleukin-12; D015847:Interleukin-4