Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.

The laminar organization of the central nucleus of inferior colliculus includes layers of axons that may be important in shaping the responses of neurons. Depending on their source, some layered axons are afferents that are superimposed and terminate on the same postsynaptic neurons, while other layered afferents, such as those from the ipsilateral and contralateral lateral superior olive, terminate side-by-side. The specific pattern of convergence may dictate which populations of axons are presynaptic to layered disc-shaped neurons in the central nucleus. We compared the distribution of afferent axons from the dorsal cochlear nucleus and the lateral superior olive to the contralateral inferior colliculus in the cat. Injection sites in cochlear nucleus and superior olive were physiologically characterized by extracellular recordings of single and multiple units in response to monaural and binaural acoustic stimulation. Two separate injections were made in each case, and both injection sites contained units with overlapping best frequencies. Biotinylated dextran, fluorescent dextran, 3H-leucine, and wheat germ agglutinin conjugated to horseradish peroxidase were used as anterograde tracers. The present results show that layered axons from the dorsal cochlear nucleus and lateral superior olive are superimposed in part of the contralateral central nucleus. Both projections were arranged in rostro-caudally oriented axonal layers that converged in the ventral part of the central nucleus. However, in the dorsal part of the central nucleus, the same layer of axons from the dorsal cochlear nucleus did not terminate with afferents from the lateral superior olive. Within the overlapping layers in the ventral central nucleus, the overlap of axons from the dorsal cochlear nucleus and the lateral superior olive was uniform except for small patches that were usually smaller than the dendritic fields of disc-shaped neurons. These data suggest that the layers may create specific functional zones in the central nucleus of the inferior colliculus. One zone may contain neurons with binaural responses that combine the properties of the inputs from the contralateral lateral superior olive and the dorsal cochlear nucleus. A second zone may contain inputs from the cochlear nucleus but lack those of the lateral superior olive.

The goal of the present study was to provide a comprehensive and quantitative description of neurons immunoreactive for gamma-aminobutyric acid (GABA) in the inferior colliculus (IC) of the cat. Neurons were investigated with two different antisera and two different incubation methods. Free-floating frozen or vibratome-cut sections were incubated either with an antiserum to glutamic acid decarboxylase (GAD) or to GABA conjugated to protein with glutaraldehyde. Additional 1.5-microns-thick sections were incubated with the GABA antiserum after embedding and removal of the plastic. Quantitative data were obtained from much of this material. Despite the use of these different antisera and reaction methods, the results obtained were remarkably similar. The results show that GAD- or GABA-positive neurons represent a significant population of cells in the central nucleus of the IC, up to 20% of the neurons. Most of these neurons have large or medium-sized perikarya. In contrast, immunonegative neurons are medium-sized or small. Many GABA-positive neurons had proximal dendrites or somata oriented in parallel to the fibrodendritic laminae of the central nucleus and are presumed to be disc-shaped neurons. Other have an orthogonal orientation and are presumed to be stellate cells. Large GABA-positive neurons form two groups, those with many axosomatic endings and those with few. Collectively, these observations suggest that there are several types of GABAergic neuron in the central nucleus and, by extension, that these may participate in many types of inhibitory circuits.

The superior olivary complex is the first site in the central auditory system where binaural interactions occur. The output of these nuclei is direct to the central nucleus of the inferior colliculus, where binaural inputs synapse with monaural afferents such as those from the cochlear nuclei. Despite the importance of the olivary pathways for binaural information processing, little is known about their synaptic organization in the colliculus. The present study investigates the structure of the projections from the lateral and medial superior olivary nuclei to the inferior colliculus at the electron microscopic level. Stereotaxic placement and electrophysiological responses to binaural sounds were used to locate the superior olive. Anterograde axonal transport of 3H-leucine was combined with light and electron microscopic autoradiography to reveal the location and morphology of the olivary axonal endings. The results show that the superior olivary complex contributes different patterns of synaptic input to the central nucleus of the inferior colliculus. Each projection from the superior olivary complex to the colliculus differs in the number and combinations of endings. Axonal endings from the ipsilateral medial superior olive were exclusively the round (R) type that contain round synaptic vesicles and make asymmetrical synaptic junctions. This morphology is usually associated with excitatory synapses and neurotransmitters such as glutamate. Endings from medial superior olive terminate densely in the central nucleus. The projection from the contralateral lateral superior olive also terminates primarily as R endings. This projection also includes small numbers of pleomorphic (PL) endings that contain pleomorphic synaptic vesicles and usually make symmetrical synaptic junctions. The PL morphology is associated with inhibitory synapses and transmitters such as gamma-aminobutyric acid and glycine. All endings from the contralateral lateral superior olive terminate much less densely than endings from the medial olive. In contrast, the projection from the ipsilateral lateral superior olive contributes both R and PL endings in roughly equal proportions. These ipsilateral afferents are heterogeneous in density and can terminate in lower or higher concentrations than endings from the contralateral side. These data show that the superior olive is a major contributor to the synaptic organization of the central nucleus of the inferior colliculus. The ipsilateral projections of the medial and lateral superior olive may produce higher concentrations of R endings than other inputs to the central nucleus. Such endings may participate in excitatory synapses. The highest concentrations of PL endings come from the ipsilateral lateral superior olive.(ABSTRACT TRUNCATED AT 400 WORDS)