Discordance in lymphoid tissue recovery following stem cell transplantation in rhesus macaques: an in vivo imaging study.
Ionizing irradiation is used routinely to induce myeloablation and immunosuppression. However, it has not been possible to evaluate the extent of ablation without invasive biopsy. For lymphoid recovery, peripheral blood (PB) lymphocytes (PBLs) have been used for analysis, but they represent <2% of cells in lymphoid tissues (LTs). Using a combination of single-photon emission computed tomography imaging and a radiotracer ((99m)Tc-labeled rhesus immunoglobulin G1 anti-CD4R1 (Fab')2), we sequentially imaged CD4(+) cell recovery in rhesus macaques following total body irradiation (TBI) and reinfusion of vector-transduced, autologous CD34(+) cells. Our results present for the first time a sequential, real-time, noninvasive method to evaluate CD4(+) cell recovery. Importantly, despite myeloablation of circulating leukocytes following TBI, total depletion of CD4(+) lymphocytes in LTs such as the spleen is not achieved. The impact of TBI on LTs and PBLs is discordant, in which as few as 32.4% of CD4(+) cells were depleted from the spleen. In addition, despite full lymphocyte recovery in the spleen and PB, lymph nodes have suboptimal recovery. This highlights concerns about residual disease, endogenous contributions to recovery, and residual LT damage following ionizing irradiation. Such methodologies also have direct application to immunosuppressive therapy and other immunosuppressive disorders, such as those associated with viral monitoring.
Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD;
Robert E
RE
Donahue
Biostatistics Research Branch, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research (FNLCR), Frederick, MD;
Sharat
S
Srinivasula
Molecular and Clinical Hematology Branch, NHLBI, NIH, Bethesda, MD;
Naoya
N
Uchida
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, FNLCR, Frederick, MD;
Insook
I
Kim
Division of Clinical Research, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD;
Alexis
A
St Claire
Division of Clinical Research, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD;
Gorka
G
Duralde
Integrated Research Facility, NIAID, NIH, Frederick, MD; and.
Paula
P
DeGrange
Integrated Research Facility, NIAID, NIH, Frederick, MD; and.
Marisa
M
St Claire
Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center.
Richard C
RC
Reba
Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD;
Aylin C
AC
Bonifacino
Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD;
Allen E
AE
Krouse
Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD;
Mark E
ME
Metzger
Radiopharmaceutical Laboratory, Nuclear Medicine, Radiology and Imaging Sciences, Clinical Center, and.
Chang H
CH
Paik
Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD.
H Clifford
HC
Lane
Molecular and Clinical Hematology Branch, NHLBI, NIH, Bethesda, MD;
John F
JF
Tisdale
Division of Clinical Research, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD;
Michele
M
Di Mascio
D000818:Animals; D001853:Bone Marrow / Q000528:radiation effects; D015704:CD4 Antigens / Q000235:genetics; D018791:CD4 Lymphocyte Count; D003199:Computer Systems; D017930:Genes, Reporter; D005813:Genes, Synthetic; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D007074:Immunoglobulin G / Q000235:genetics; D016086:Lentivirus / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology / Q000528:radiation effects; D008221:Lymphoid Tissue / Q000000981:diagnostic imaging / Q000502:physiology* / Q000528:radiation effects; D008253:Macaca mulatta; D064847:Multimodal Imaging; D009928:Organ Specificity; D011828:Radiation Chimera; D013154:Spleen / Q000276:immunology / Q000528:radiation effects; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D014161:Transduction, Genetic; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D014916:Whole-Body Irradiation
D015704:CD4 Antigens; D007074:Immunoglobulin G; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins