ABSTRACT
The metastatic ESb-MP murine lymphoma in DBA/2 mice has been used as a model for investigating metastatic disease and its cure by adoptive immunotherapy (ADI) as monitored by in vivo multislice spin-echo 1H NMR microimaging at 7 T. isoflurane inhalation anesthesia facilitated long measurement sessions, and respiratory gating with a fiber-optic sensor greatly reduced motional artifacts. With T2 weighting (TR = 2 s, TE = 30 ms) mean signal-to-noise ratios of 30 and 15 for kidney and liver, respectively, were achieved in 20 min (100-micron pixels, 1-mm slices, 25-mm field of view). Without the use of contrast agents, metastases with diameters > or = 0.3 mm in the imaged plane could be detected as hyperintense lesions in kidney (contrast ratio ca. 1.4) and liver (contrast ratio ca. 2) with a confidence level of > 98%. For the first time the complete eradication of late-stage macroscopic metastases by ADI could be demonstrated noninvasively by MRI.
Subject(s)
Immunotherapy, Adoptive , Kidney Neoplasms/secondary , Liver Neoplasms/secondary , Lung Neoplasms/secondary , Lymphoma/diagnosis , Magnetic Resonance Spectroscopy/methods , Respiration/physiology , Animals , Artifacts , Disease Models, Animal , Disease Progression , Female , Follow-Up Studies , Kidney Neoplasms/physiopathology , Kidney Neoplasms/therapy , Liver Neoplasms/physiopathology , Liver Neoplasms/therapy , Lung Neoplasms/physiopathology , Lung Neoplasms/therapy , Lymphoma/physiopathology , Lymphoma/therapy , Mice , Mice, Inbred DBA , Treatment OutcomeABSTRACT
The intradermal ESb-MP murine T-cell lymphoma in syngeneic DBA/2 mice has been used as a model for adoptive immunotherapy (ADI). Cultured ESb-MP cells were characterized in suspension by 31P-NMR spectroscopy (MRS) at 11.7 T, and solid primary tumors were examined by 31P-MRS in vivo at 7.0 Tesla using surface-coil techniques. Growing tumors contained relatively high levels of phosphomonoesters (PME, predominantly phosphoethanolamine), nucleotides (NTP) and Pi, low levels of phosphodiesters (PDE) and no phosphocreatine. Mean tissue pH was found to be 6.7-6.9. The spectra of ESb-MP cells cultured in RPMI medium (containing choline but no ethanolamine) also showed low PDE and no phosphocreatine at an intracellular pH of 7.4; however, only a trace amount of phosphoethanolamine was detected and significant levels of nucleoside mono- and diphosphates were observed. The complete ADI treatment protocol involved low-dose irradiation (5 Gy) followed by i.v. transfer of immune spleen cells from allogeneic B10.D2 donors and resulted in 100% remission (responders); no treatment or incomplete ADI (irradiation or immune cell transfer alone) resulted in no remissions (nonresponders). In vivo MRS could best discriminate between responders and non-responders on the basis of tissue pH, which increased in responders to 7.0 by day 5-6 after complete ADI. Following therapy, the sum of PME + Pi (both absolute and as a percent of total phosphates) decreased significantly only for responders but only after a visible decrease in tumor volume was apparent.
