Rituximab Efficiently Depletes Increased CD20-Expressing T Cells in Multiple Sclerosis Patients.
Palanichamy A, Jahn S, Nickles D, Derstine M, Abounasr A, Hauser SL, Baranzini SE, Leppert D, von Büdingen HC.
In multiple sclerosis (MS), B cell-depleting therapy using monoclonal anti-CD20 Abs, including rituximab (RTX) and ocrelizumab, effectively reduces disease activity.
Based on indirect evidence, it is generally believed that elimination of the Ag-presenting capabilities and Ag nonspecific immune functions of B cells underlie the therapeutic efficacy.
However, a small subset of T lymphocytes (T cells) was shown to also express CD20, but controversy prevails surrounding the true existence of this T cell subpopulation. Using single-cell imaging flow cytometry and expression profiling of sorted lymphocyte subsets, we unequivocally demonstrate the existence of CD3+CD20dim T cells.
We show that in MS patients, increased levels of CD3+CD20dim T cells are effectively depleted by RTX. The pathological relevance of this T cell subset in MS remains to be determined.
However, given their potential proinflammatory functionality, depletion of CD20-expressing T cells may also contribute to the therapeutic effect of RTX and other mAbs targeting CD20.
Sources: J Immunol. 2014 Jun 13. pii: 1400118. [Epub ahead of print] & Pubmed PMID: 24928997 (16/06/14)
There are currently no effective treatments for people with secondary-progressive MS who do not experience relapses or who do not have “active” lesions on MRI, however researchers at the National Institutes of Health in Bethesda, Maryland are evaluating the safety and effectiveness of Rituximab (trade names Rituxan and MabThera) – a new experimental drug for treating MS. In this study, Rituximab be delivered intravenously and directly into the cerebrospinal fluid by lumbar puncture of about 80 people with secondary-progressive Multiple Sclerosis. The study is funded by the National Institute of Neurological Disorders and Stroke.
Technically, Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences. Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids.
Since MS is an inflammatory disorder that progressively weakens and destroys the pathways of the nervous system. There are currently no effective treatments for people with secondary-progressive MS who do not experience relapses or who do not have “active” lesions identified via MRI.
Under normal conditions, the blood brain barrier separates the brain and spinal cord from the bloodstream and limits what can gain access to the nervous system. In active stages of MS, inflammation in the brain and spinal cord leads to breakdown of this barrier. This breakdown allows MS medications to reach the brain and spinal cord without being screened out. In people with secondary-progressive MS who do not have “active” disease, the blood-brain barrier is intact. Drugs that could stop the inflammation simply cannot reach the areas of the brain and spinal cord where they are needed.
The NIH researchers want to understand whether Rituximab, which is already used to treat rheumatoid arthritis (another autoimmune disease) and some types of cancer, is able to slow down or stop progression of secondary-progressive MS. In people with earlier, active disease, this drug can stop inflammation in the brain. However, intravenous Rituximab did not help people with primary-progressive MS (typical, as forenoted), possibly because the drug could not get through the intact blood-brain barrier. In this current trial, to ensure that the Rituximab will reach the brain and spinal cord in people with secondary-progressive MS, participants will receive it intravenously and by injection through a lumbar puncture into the cerebrospinal fluid (“spinal tap”).
Participants in the NIH study will be between 18 and 65 years of age, diagnosed with secondary-progressive MS, and able to walk for 25 feet with assistance. The study will last three years and will be divided into two parts. The first part is a 1-year baseline period during which participants will not be treated. The second part is a 2-year treatment period during which there will be a total of 3 infusions with either Rituximab or placebo. Participants will have periodic follow-up clinic visits that will include brain magnetic resonance imaging (MRI) scans, blood tests, and other evaluations. There will be approximately 7 outpatient clinic visits. Outpatient clinic visits will last 2-5 hours. The three infusion visits will each require a 2-3 day admission to the NIH Clinical Center.
The study’s primary outcome objective is to determine whether Rituximab can decrease brain atrophy – loss of brain tissue volume – significantly more than a placebo. There is no cost to take part in this study. Reimbursement for travel, lodging, and food will be offered. People participating in the study will not receive payment.
Source: BioNews Texas (27/01/14)