The relationship between the delayed-type hypersensitivity (DTH) response and susceptibility to experimental allergic encephalomyelitis (EAE) was examined using a unique age-dependent defect in the DTH response in an EAE-susceptible mouse strain. Young adult male SJL mice ( < 10 weeks of age) are defective in DTH responses following immunization with a variety of soluble antigens. By contrast, they respond to antigens applied to the skin, demonstrating a normal contact sensitivity response. In this report, we show that the non-responder male SJL are also unable to mount a DTH response to soluble neuroantigens or neuroantigens emulsified in complete adjuvant, and are additionally resistant to actively induced EAE. This contrasts with the DTH response in older males ( > 10 weeks of age) and young adult females (6 weeks of age), which are both DTH responders and susceptible to EAE. By contrast, all three groups are susceptible to EAE mediated by the transfer of activated effector T cells, suggesting that the defect in young adult males is in the induction of effectors. Furthermore, transfer of a macrophage population from female responders to young male non-responders mediates the induction of both DTH responsiveness and EAE susceptibility. The phenotype of this antigen-presenting cell is (I-A+, Mac-1+, Mac-2-, Mac-3+), identical to the phenotype of the macrophage regulating DTH responsiveness in this strain of mice. These data are consistent with the hypothesis that a defect in this cell inhibits induction of both CD4+Th1 DTH and EAE effector T cells.

Squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Previous studies suggested that circulating amyloid-beta40 peptide (Abeta40) crosses the blood-brain barrier (BBB) and may therefore enhance cerebrovascular amyloidosis in aged squirrel monkeys. In the present study, we used single photon emission computed tomography (SPECT) to determine elimination of 123I-Abeta40 and 99mTc-DTPA, an extracellular marker, from the brain in squirrel monkeys at different age. Following intracerebral microinfusions, the time-activity brain clearance curves indicated bi-exponential removal of 123I-Abeta40 with an initial rapid washout (1.1 < or = t 1/2 < or = 2.7 h). This, plus the observed appearance of 123I-radioactivity in plasma suggest significant brain-to-blood transport. In contrast, 99mTc-DTPA was removed slowly by brain interstitial fluid bulk flow (monoexponential decay with 6.8 < or = t 1/2 < or = 16.8 h). A comparison of three middle aged (11-16 years old) vs. two old (22 yrs old) monkeys was consistent with an age-related decline in the BBB capacity to remove 123I-Abeta from the brain. This correlated with an age-dependent increase in A1beta40/42 cerebrovascular immunoreactivity and amyloid deposition. Thus, vascular clearance plays an important role in reducing Abeta levels in the squirrel monkey brain and impaired Abeta40 elimination across the BBB may contribute to the development of CAA.

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