Guest Post: Professor Michael Pender

Professor Michael Pender explains how anti-EBV cell therapy works in MS. #MSBlog #MSResearch

"At the request of one of you and following on from his recent publication on treating EBV by transfer of virus killing T cells we asked Prof. Michael Pender from Australia to give you more details on his group's work."

Professor Michael Pender graduated from The University of Queensland in 1974 with First Class Honours in Medicine and a University Medal. Over the next six years he trained as a physician and neurologist at the Royal Prince Alfred Hospital and St Vincent's Hospital, Sydney, and became a Fellow of the Royal Australasian College of Physicians in 1981. During his clinical training he developed a keen interest in multiple sclerosis which has continued since then. 

After completing clinical training in neurology, he commenced research on experimental autoimmune encephalomyelitis under the supervision of Professor Tom Sears at the Institute of Neurology, Queen Square, London. In 1983 he was awarded a PhD from the University of London and Queen Square Prize for Research. From 1984-1986 he continued this research as a Research Fellow at the John Curtin School of Medical Research, Australian National University, Canberra, in the Department of Experimental Pathology chaired by Professor Peter Doherty, Nobel laureate. In 1987 he was appointed Senior Lecturer in the Department of Medicine, The University of Queensland, at the Royal Brisbane Hospital. In 1989 he was awarded a Doctorate of Medicine from The University of Queensland for research on experimental autoimmune encephalomyelitis and was promoted to Reader in Medicine. In 1995 he was promoted to Professor of Medicine (Personal Chair), The University of Queensland. He also held the position of Director of Neurology, Royal Brisbane and Women's Hospital, from 1992-2005. He is Director of The University of Queensland Multiple Sclerosis Research Centre and an Honorary Senior Principal Research Fellow at the QIMR Berghofer Medical Research Institute, and directs the Multiple Sclerosis Clinic at the Royal Brisbane and Women's Hospital. In 2006 he was awarded the Multiple Sclerosis Australia Prize for Multiple Sclerosis Research - 'For outstanding commitment and dedication to research into the cause and cure of Multiple Sclerosis in Australia'. In 2011 he received the John H Tyrer Prize in Internal Medicine, The University of Queensland, for research in the field of Internal Medicine.

Professor Pender writes
A large body of evidence indicates that infection with Epstein-Barr virus (EBV) has a role in the development of multiple sclerosis (MS). EBV infects B cells and plasma cells, the white blood cells that make antibodies. Once a person is infected with EBV, they carry the virus in their B cells for the rest of their life. Normally the number of EBV-infected B cells is kept under tight control by the immune system especially by CD8+ T cells, which kill the infected cells. 
In 2003 I published a new theory in Trends in Immunology proposing that chronic autoimmune diseases such as MS and rheumatoid arthritis are caused by uncontrolled EBV infection leading to infection of autoreactive B cells, which accumulate in the organ affected by the autoimmune disease. I proposed that MS was caused by the accumulation in the brain of EBV-infected autoreactive B cells which produce anti-brain antibodies and also provide survival signals to autoreactive T cells that would otherwise die in the brain by apoptosis (programmed cell death). The theory made predictions which have subsequently been verified, namely: the presence of EBV-infected B cells in the brain in MS; a beneficial effect of rituximab which kills B cells, including EBV-infected B cells; decreased CD8+ T cell immunity to EBV in MS; and EBV infection of autoreactive plasma cells in the joints of people with rheumatoid arthritis. It also predicted that boosting CD8+ T cell control of EBV by vaccination or by adoptive immunotherapy would prevent and successfully treat chronic autoimmune diseases.

EBV-specific adoptive immunotherapy involves growing T cells from the blood in the laboratory with an EBV vaccine to retrain the cells to be potent killers and then returning them to the patient by intravenous infusion. This treatment was developed by Professor Rajiv Khanna of the QIMR Berghofer Medical Research Institute in Brisbane to treat patients with EBV-related malignancy and does not require the use of any drugs. Professor Khanna and his team have successfully used this therapy to treat EBV-related metastatic nasopharyngeal carcinoma. This EBV vaccine expresses parts of three EBV proteins, which are crucial in allowing EBV-infected B cells to multiply and mature into memory B cells and plasma cells capable of producing large amounts of antibody. As it happens, Francesca Aloisi’s group have shown that these same three EBV proteins are the main EBV proteins present in the brain-infiltrating EBV-infected B cells in MS.

EBV-specific adoptive immunotherapy has not previously been used to treat people with MS or any other autoimmune disease. Because we were concerned that the therapy might aggravate inflammation in the brain and actually worsen MS, we reduced the initial dose of T cells to 25% of the dose used by Professor Khanna to treat EBV-related malignancy. We then gradually increased the dose over the next three infusions, which were administered at fortnightly intervals. The first recipient was a 42 year old man with secondary progressive MS. The treatment had no adverse effects and within 2 weeks the patient began to experience clinical improvement. This was followed by further improvement, with a reduction in fatigue and painful lower limb spasms, an improvement in cognition and hand function, and increased productivity at work. These improvements were sustained up to the time of the latest review, 21 weeks after the final T cell infusion, when neurological examination demonstrated increased movement of his legs. There was also reduced disease activity on his MRI brain scan and reduced antibodies in the cerebrospinal fluid.

We believe that the beneficial effects of the therapy are due to the killing of EBV-infected B cells in the brain by the transferred CD8+ T cells. The beneficial effect of boosting immunity to EBV by this treatment highlights the importance of impaired immunity to EBV in the development of MS. A clinical trial is now needed to determine safety and therapeutic efficacy across the clinical spectrum of MS.

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