Avertano Noronha, M.D., Ph.D.

Neuroimmunology; Multiple Sclerosis

Research Summary

My field of interest is clinical neuroimmunology with a focus on Multiple Sclerosis (MS). Research in my laboratory is directed towards studying T cell activation in MS and in the animal model, EAE. In the past year, we have made progress in both projects as shown below.

Project 1. CNS-derived T cells in EAE. We have previously reported that T cells that infiltrate the spinal cord in EAE are activated Th1 cells and that Th1 clones transfer EAE. In the past year, we have shown that CNS-derived T cells become unresponsive with respect to proliferation and IL2 secretion at the peak of disease and during recovery. Analysis of the cytokine profile of infiltrating T cells shows that Th1 cells which are numerous at disease onset are profoundly suppressed as recovery ensues and do not make IL2. In addition, significant number of T cells are detected in the CNS and they respond to stimulation by secreting IFN and IL4, but not IL2. These findings indicate a shift of the immune response from Th1 to Th2 and may explain how acute EAE is terminated, and by corollary, offer a mechanism for the termination of the acute attack in MS.

Project 2: Modulation of immune function in MS patients treated with IFN-beta 1b. We have previously shown that IFN-beta 1b modulates suppressor function and release of cytokines in vitro effect of Betaseron and the kinetics of this effect. We find that at 4 weeks after therapy, IFN- and TNF levels are decreased, similar to our in vitro findings.

In collaboration with Gijs van Seventer, we have examined the expression of several cell surface and adhesion molecules on peripheral blood cells from MS patients treated with Betaseron. We found that expression of 41, an integrin that mediates the ingress of activated Th1 cells into the CNS in EAE was lower in Betaseron-treated patients; the mechanism of this effect is being actively investigated.

Clinical Research: I participate in clinical drug trials in MS and these are listed below. In addition to determining a clinical effect of the experimental drugs, my laboratory studies the effect of the drugs on the immune system in vivo.

Investigational drug trials: Double-blind, randomized, placebo-controlled, parallel group study of the safety and efficacy of Ro 45-2081 (TNF-receptor fusion protein) in patients with relapsing-remitting multiple sclerosis. F. Hoffman LaRoche, Ltd.

Double-blind, placebo-controlled phase 3 study to evaluate the safety and efficacy of Betaseron given subcutaneously to patients with progressive multiple sclerosis. Berlex Laboratories.

A randomized, double-blind, placebo-controlled, phase 3 study of Roquinimex (Linomide) in relapsing-remitting and secondary progressive multiple sclerosis. Pharmacia.

Selected Papers

Noseworthy JH, Wolinsky JS, Lublin FD, Whiakter Jn, Linde A, Gjorstrup P, Sullivan HC, and the North American Linomide Investigators.  (2000). Linomide in relapsing and secondary progressive MS:  Part I.  Trial design and clinical results.  Neurology 54:1726-1733.

Wolinsky JS, Narayana PA, Noseworthy JH, Lulin FD, Whitaker JN, Linde A, Gjorstrup P, Sullivan HC, and the MRI Analysis Center of the University of Texas-Houston, Health Science Center for the North American Linomide Investigators. (2000). Linomide in relapsing and secondary progressive Multiple Sclerosis: II.  MRI results.  Neurology 54:1734-1741.

The Lercept Multiple Sclerosis Study Group and the University of British Columbia Columbia MS/mri Analysis Group.  TNF neutralization in MS:  results of a randomized, placebo-controlled multicenter study.  (Submitted)

Petkau AJ, White R, Ebers GC, Reder AT, Sibley WA, Lublin FD, Paty DW, and the IFNB Multiple Sclerosis Study Group.  Longitudinal analyses of the effects of neutralizing antibodies in relapsing-remitting multiple sclerosis patients treated with interferon beta-1b. (Submitted).