Effect of highly active antiretroviral therapy and thymic transplantation on immunoreconstitution in HIV infection.
The purpose of this study was to determine whether thymic transplantation in addition to highly active antiretroviral therapy (HAART) will restore T cell function in HIV infection. Eight treatment-naive HIV-infected patients with CD4+ T cell counts of 200-500/mm3 were randomized into thymic transplantation and control arms. All patients received HAART (zidovudine, lamivudine, and ritonavir) for 6 weeks prior to transplantation. Thymic transplantation was done without immunosuppression, using postnatal HLA-unmatched cultured allogeneic thymus tissue. Patients were immunized every 6 months with the neoantigen keyhole limpet hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). T cell phenotype and function and T cell receptor rearrangement excision circles (TRECs) were assessed. Thymic allografts were biopsied at 2 months. Six HIV-infected patients completed the study. Four patients received cultured allogeneic postnatal thymic grafts, two others were controls. CD4+ T cell counts increased and T cell-proliferative responses to Candida antigen and TT normalized in all patients. Proliferative responses to KLH developed in three of four transplant recipients and one of two controls. Patients responding to KLH after secondary immunization had greater TREC increases compared with the patients who did not respond. All thymic allografts were rejected within 2 months. In summary, four of six patients developed T cell-proliferative responses to the neoantigen KLH over the first 2 years of HAART. The transplanted thymus tissue, however, was rejected. There was no clear difference in restoration of T cell function in the transplant recipients compared with the controls. Increases in TRECs after initiation of HAART may correlate with improved immune function.
Markert
M L
ML
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA. marke001@mc.duke.edu
Hicks
C B
CB
Bartlett
J A
JA
Harmon
J L
JL
Hale
L P
LP
Greenberg
M L
ML
Ferrari
G
G
Ottinger
J
J
Boeck
A
A
Kloster
A L
AL
McLaughlin
T M
TM
Bleich
K B
KB
Ungerleider
R M
RM
Lyerly
H K
HK
Wilkinson
W E
WE
Rousseau
F S
FS
Heath-Chiozzi
M E
ME
Leonard
J M
JM
Haase
A T
AT
Shaw
G M
GM
Bucy
R P
RP
Douek
D C
DC
Koup
R A
RA
Haynes
B F
BF
Bolognesi
D P
DP
Weinhold
K J
KJ
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D001706:Biopsy; D018791:CD4 Lymphocyte Count; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D015329:Gene Rearrangement, T-Lymphocyte / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000601:surgery / Q000628:therapy*; D006433:Hemocyanins / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D010641:Phenotype; D039102:Poly(A)-Binding Proteins; D011506:Proteins; D012367:RNA, Viral / Q000032:analysis; D016601:RNA-Binding Proteins / Q000378:metabolism; D000074019:T-Cell Intracellular Antigen-1; D013745:Tetanus Toxoid / Q000008:administration & dosage; D013950:Thymus Gland / Q000637:transplantation*; D014184:Transplantation, Homologous
D019380:Anti-HIV Agents; D008565:Membrane Proteins; D039102:Poly(A)-Binding Proteins; D011506:Proteins; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; D013745:Tetanus Toxoid; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin