Stable multilineage chimerism without graft versus host disease following nonmyeloablative haploidentical hematopoietic cell transplantation.
BACKGROUND
Hematopoietic cell transplantation may offer the only cure for patients with hematological diseases. The clinical application of this therapy has been limited by toxic conditioning and lack of matched donors. Haploidentical transplantation would serve to extend the potential donor pool; however, transplantation across major histocompatibility complex barriers is often associated with severe graft-versus-host disease. Here we evaluate a novel protocol to achieve engraftment across mismatch barriers without toxic conditioning or significant posttransplant complications.


METHODS
Nine major histocompatibility complex (MHC)-defined miniature swine received haploidentical hematopoietic cell transplantation following standard myeloablative conditioning. Nine additional animals received haploidentical hematopoietic cell transplantation following a minimally myelosuppressive regimen, consisting of 100 cGy total body irradiation, immunotoxin mediated T-cell depletion, and a short course of cyclosporine. Donor cell engraftment and peripheral chimerism was assessed by polymerase chain reaction and flow cytometry. Graft-versus-host disease was monitored by clinical grading and histology of skin biopsy specimens.


RESULTS
All animals conditioned for haploidentical hematopoietic cell transplantation using myeloablative conditioning were euthanized within 2 weeks due to engraftment failure or graft-versus-host disease. All animals conditioned with the nonmyeloablative regimen developed multilineage peripheral blood chimerism during the first 2 months following transplantation. Six animals evaluated beyond 100 days maintained multilineage chimerism in the peripheral blood and lymphoid tissues, showed evidence of progenitor cell engraftment in the bone marrow, and had minimal treatment-related complications.


CONCLUSIONS
Here we report that stable multilineage chimerism and engraftment can be established across haploidentical major histocompatibility complex barriers with minimal treatment-related toxicity and without significant risk of graft-versus-host disease.
Cina
Robert A
RA
Transplantation Biology Research Center-Surgery, Massachusetts General Hospital, Boston, MA 02129, USA.
Wikiel
Krzysztof J
KJ
Lee
Patricia W
PW
Cameron
Andrew M
AM
Hettiarachy
Shehan
S
Rowland
Haley
H
Goodrich
Jennifer
J
Colby
Christine
C
Spitzer
Thomas R
TR
Neville
David M
DM
Huang
Christene A
CA
D000818:Animals; D019070:Cell Lineage / Q000235:genetics*; D046528:Chimerism; D003114:Colony-Forming Units Assay; D006086:Graft vs Host Disease; D042381:Granulocyte Precursor Cells / Q000473:pathology / Q000528:radiation effects; D006238:Haploidy; D018380:Hematopoietic Stem Cell Transplantation; D018655:Lymphocyte Count; D010976:Platelet Count; D013552:Swine; D013950:Thymus Gland / Q000378:metabolism; D019172:Transplantation Conditioning; D016896:Treatment Outcome