[Mesenchymal stem cells for treatment of steroid-resistant chronic graft-versus-host disease].
OBJECTIVE
To assess whether treatment with mesenchymal stem cells (MSCs) is an effective adjunct therapy for refractory extensive chronic graft-versus-host disease (GVHD) resistant to conventional therapy.


METHODS
12 patients with steroid-resistant extensive chronic GVHD were treated with MSCs. One patient received one dose, 10 received two doses, and the remaining three doses. The MSCs were obtained from HLA-identical sibling donors (n = 14), haploidentical donors (n = 2), unrelated mismatched donor (n = 1) and third-party HLA-mismatched donors (n = 7). Of the 11 patients treated with multiple infusions, 5 received cells derived from two donors. The median first dose of MSCs was 1.0 (0.4-2.1) x 10(6)/kg, the median second dose was 1.2 (0.8-1.9) x 10(6)/kg , and the third dose in one patient was 1.1 x 10(6)/kg. Meanwhile the proportion of CD3+, CD4+, CD8+, CD19+, CD4+, CD25+, FOXP3+, FOXP3+ CD4+ and FOXP3 + CD25+ was determined with double fluorescent-labeled antibodies and flow cytometry before and 4 weeks after the MSCs infusion.


RESULTS
No patients had side-effects during or immediately after the infusions of MSCs. After a treatment course of one to three doses, 3 patients had complete response( CR), 6 showed partial response (PR) and 3 did not respond; the total effective rate was 75% (9/12). Complete resolution was seen in the involvement of skin (3/12), lung (1/3), joints (1/5), liver (3/10), oral cavity (4/12) and eye (2/7). Response rate was not related to donor HLA-match. 3 CR patients discontinued all of the immunosuppressive agents without relapse 100 to 292 days after the MSC infusion and 6 PR patients taped all immunosuppressive agents after 60 to 79 days. Mean follow-up period was 1152 (795-1914) days, leukemia free survival rate was 91.7% (11/12) and the overall survival rate was 75% (9/12). The ratio of CD4/CD8 and the proportion of regulatory T cells were significantly higher than that before MSCs treatment.


CONCLUSIONS
Third-party MSCs were as effective as HLA-identical or haploidentical cells. This finding has practical implications and suggests that third-party cells can be prepared and stored frozen to be used for steroid-resistant extensive chronic GVHD therapy. It is concluded that MSCs may prevent the lethal cGVHD after allogeneic hematopoietic stem cell transplantation and raise the survival rate by increasing the ratio of CD4/CD8 and proportion of regulatory T cells in vivo.
Zhang
Le-Shi
LS
Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Liu
Qi-Fa
QF
Huang
Ke
K
Zhang
Yu
Y
Fan
Zhi-Ping
ZP
Huang
Shao-Liang
SL
D000293:Adolescent; D000328:Adult; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000517:prevention & control* / Q000628:therapy*; D006801:Humans; D007938:Leukemia / Q000601:surgery; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D016896:Treatment Outcome; D055815:Young Adult
D005938:Glucocorticoids