Mixed chimerism and immunosuppressive drug withdrawal after HLA-mismatched kidney and hematopoietic progenitor transplantation.
BACKGROUND
Rodents and dogs conditioned with total-lymphoid irradiation (TLI), with or without antithymocyte globulin (ATG), have been shown to develop mixed chimerism and immune tolerance without graft-versus-host disease (GVHD) after the infusion of major histocompatability complex (MHC)-mismatched donor bone marrow cells given alone or in combination with an organ allograft.


METHODS
Four human leukocyte antigen (HLA)-mismatched recipients of living donor kidney transplants were conditioned with TLI and ATG posttransplantation and infused with cyropreserved donor granulocyte colony-stimulating factor (G-CSF) "mobilized" hematopoietic progenitor (CD34+) cells (3-5x10(6) cells/kg) thereafter. Maintenance prednisone and cyclosporine dosages were tapered, and recipients were monitored for chimerism, GVHD, graft function, T-cell subsets in the blood, and antidonor reactivity in the mixed leukocyte reaction (MLR).


RESULTS
Three of the four patients achieved multilineage macrochimerism, with up to 16% of donor-type cells among blood mononuclear cells without evidence of GVHD. Prolonged depletion of CD4+ T cells was observed in all four patients. Rejection episodes were not observed in the three macrochimeric recipients, and immunosuppressive drugs were withdrawn in the first patient by 12 months. Prednisone was withdrawn from a second patient at 9 months, and cyclosporine was tapered thereafter.


CONCLUSIONS
Multilineage macrochimerism can be achieved without GVHD in HLA-mismatched recipients of combined kidney and hematopoietic progenitor transplants. Conditioning of the host with posttransplant TLI and ATG was nonmyeloablative and was not associated with severe infections. Recipients continue to be studied for the development of immune tolerance.
Millan
Maria T
MT
Department of Surgery, Division of Transplantation, Stanford University School of Medicine, Stanford, CA 94305, USA.
Shizuru
Judith A
JA
Hoffmann
Petra
P
Dejbakhsh-Jones
Sussan
S
Scandling
John D
JD
Grumet
F Carl
FC
Tan
Jane C
JC
Salvatierra
Oscar
O
Hoppe
Richard T
RT
Strober
Samuel
S
D000328:Adult; D001787:Blood Group Incompatibility; D004334:Drug Administration Schedule; D005260:Female; D006680:HLA Antigens / Q000032:analysis*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D007958:Leukocyte Count; D015182:Lymphatic Irradiation; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000473:pathology; D018183:Transplantation Chimera; D014181:Transplantation Immunology / Q000235:genetics*; D016896:Treatment Outcome
D006680:HLA Antigens; D007166:Immunosuppressive Agents