Immune 2: Lymphocytes after dark

Cindy, Steph, and Vincent reveal that lymphocyte trafficking through lymph nodes and lymph is circadian – it is dependent on the time of day.

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The $475,000 drug

KymriahThe US Food and Drug Administration recently approved the first gene therapy, Kymriah, to treat B-cell acute lymphoblastic leukemia. It uses a lentivirus to modify the patient’s T cells to kill tumor cells.

Acute lymphoblastic leukemia, or ALL, is caused by uncontrolled growth of B cells, which normally produce antibodies to fight off infections. It is the most common cancer in children. The uncontrolled production of these cells by the bone marrow causes a shortage of blood cell production, leading to fever, increased risk of infection, and anemia. These B cells have on their surfaces a protein called B19 – which is the key to understanding how Kymriah works.

The therapy begins with drawing blood from the patient, from which T cells are purified. These T cells are then infected with a lentivirus vector that encodes the gene for a chimeric antigen receptor (CAR) that recognizes the B19 protein. The CAR protein is synthetic – it doesn’t exist in any cell. The extracellular domain consists of a single-chain antibody directed against the B19 protein (pictured). The cytoplasmic domain of the protein contains sequences that stimulate the T cells to proliferate.

After the T cells are infected with the CAR-encoding lentivirus, they are infused back into the patient. Upon encountering a B cell producing B19, the T cells bind to the protein and kill the cells, thus eliminating the cancer.

Kymriah was licensed by the FDA after testing showed it was effective, leading to remission of cancers in the majority of children treated. But the price tag is steep – $475,000 for a treatment, and other similar drugs in the pipeline could be even more expensive. The drug makers justify the high price by arguing that it reflects the value to the patient – it saves their lives.

But vaccines also save lives, and they cost much less than Kymriah. The difference, of course, is that vaccines are given to millions of people. Kymriah, in contrast, would be given to thousands in the US.

In other words, the high cost of Kymriah reflects the need of drug companies to recoup their high investment in developing and testing the drug – not the value to the patient.  Rather than spinning a false story about the value of a drug to a patient, the drug companies should be honest about the pricing of their products. No wonder the public has a negative image of the industry.

TWiV 345: How a vaccine got the nod

On episode #345 of the science show This Week in Virology, the TWiVonauts review how the weather affects West Nile virus disease in the US, benefit of B cell depletion for ME/CFS patients, and an autoimmune reaction induced by influenza virus vaccine that leads to narcolepsy.

You can find TWiV #345 at

B cell depletion benefits ME/CFS patients

B cellPatients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) showed clinical improvement after extended treatment with the anti-B-cell monoclonal antibody rituximab. This result suggests that in a subset of patients, ME/CFS might be an autoimmune disease.

Rituximab is a monoclonal antibody against a protein on the surface of B cells known as CD20. When the antibody is given to patients, it leads to destruction of B cells, which are the producers of antibodies, proteins that are made by the immune system to counter infections. The drug has been approved by the US Food and Drug administration to treat diseases of B cells such as lymphomas, leukemias, and autoimmune conditions.

ME/CFS is a disease of unknown etiology and mechanism that includes symptoms of severe fatigue, post-exertional malaise, pain, cognitive and sleep problems that affects 0.1-0.2% of the population. A previous randomized, phase II trial of rituximab treatment showed clinical benefit in 20 of 30 patients. The improvements were evident 2-8 months after treatment, leading the study authors to suggest that remission requires elimination of long-lived antibodies after depletion of B cells.

The current study was done to determine the effects of sustained treatment with rituximab. Included patients (29) were 18-66 years of age and diagnosed with ME/CFS according to Fukuda 1994 criteria. All were given rutiximab infusions two weeks apart, then at 3, 6, 10, and 15 months, and followed up for 36 months. Self-reported symptoms were recorded every second week and used to calculate scores for fatigue (comprising post-exertional malaise, need for rest, daily functioning), pain (muscle, joint, and cutaneous pain and headache) and cognitive scores (concentration ability, memory disturbance, mental tiredness).

Clinically significant responses were found in 18/29 patients (64%), with a lag of 8-66 weeks. After 36 weeks 11 of 18 responding patients were still in clinical remission. Nine patients from the placebo group in the previous study were included in this trial; of these, six had clinical improvement.

These results show that some ME/CFS patients benefit from ablating B cells. The delayed response, coupled with the relapse after cessation of treatment and B cell regeneration, suggests that antibodies are involved in the pathogenesis of the disease. Because onset of ME/CFS in many patients correlates with a viral infection, it is possible that antibodies to viral proteins may cross-react with self proteins, leading to autoimmune reactions that cause disease. Treatment with rituximab would lead to reduced levels of such antibodies, thereby reducing symptoms.

These results warrant trials of larger numbers of ME/CFS patients in other countries (this study was carried out in Norway) to determine if ablation of B cells would have a similar effects elsewhere. It would also be useful to determine the total repertoire of antiviral antibodies produced by ME/CFS patients. Such antibodies can be identified using the newly developed VirScan assay, which requires a small amount of blood and is relatively inexpensive. The results will indicate whether certain viral infections in a large population of ME/CFS patients predispose to the illness. Furthermore, the results may also be used to guide efforts to determine whether such antibodies react with human cellular proteins. A similar approach was used to determine that antibodies to an influenza virus protein cross react with a neuropeptide receptor, leading to narcolepsy.

While these findings are promising, they also show that not all ME/CFS may involve autoimmune pathogenesis. Other creative approaches will be needed to determine the cause of disease in individuals who do not respond to rituximab.

TWiV 312: She sells B cells

On episode #312 of the science show This Week in Virology, the TWiVbolans discuss the finding that human noroviruses, major causes of gastroenteritis, can for the first time be propagated in B cell cultures, with the help of enteric bacteria.

You can find TWiV #312 at

TWiV 161: Concerto in B

antibodyHosts: Vincent Racaniello, Rich ConditAlan Doveand Gabriel Victora

Vincent, Rich, Alan and Gabriel review the production of antibodies by B cells, and how high affinity antibodies are selected in the germinal centers of lymph nodes.

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Adaptive immune defenses

adaptive-immune-systemThe immune response to viral infection comprises innate and adaptive defenses. The innate response, which we have discussed previously, functions continuously in a normal host without exposure to any virus. Most viral infections are controlled by the innate immune system. However, if viral replication outpaces innate defenses, the adaptive response must be mobilized.

The adaptive defense consists of antibodies and lymphocytes, often called the humoral response and the cell mediated response. The term ‘adaptive’ refers to the differentiation of self from non-self, and the tailoring of the response to the particular foreign invader. The ability to shape the response in a virus-specific manner depends upon communication between the innate and adaptive systems. This communication is carried out by cytokines that bind to cells, and by cell-cell interactions between dendritic cells and lymphocytes in lymph nodes. This interaction is so crucial that the adaptive response cannot occur without an innate immune system.

The cells of the adaptive immune system are lymphocytes – B cells and T cells. B cells, which are derived from the bone marrow, become the cells that produce antibodies. T cells, which mature in the thymus, differentiate into cells that either participate in lymphocyte maturation, or kill virus-infected cells.

Both humoral and cell mediated responses are essential for antiviral defense. The contribution of each varies, depending on the virus and the host. Antibodies generally bind to virus particles in the blood and at mucosal surfaces, thereby blocking the spread of infection. In contrast, T cells recognize and kill infected cells.

A key feature of the adaptive immune system is memory. Repeat infections by the same virus are met immediately with a strong and specific response that usually effectively stops the infection with less reliance on the innate system. When we say we are immune to infection with a virus, we are talking about immune memory. Vaccines protect us against infection because of immune memory. The first adaptive response against a virus – called the primary response – often takes days to mature. In contrast, a memory response develops within hours of infection. Memory is maintained by a subset of B and T lymphocytes called memory cells which survive for years in the body. Memory cells remain ready to respond rapidly and efficiently to a subsequent encounter with a pathogen. This so-called secondary response is often stronger than the primary response to infection. Consequently, childhood infections protect adults, and immunity conferred by vaccination can last for years.

The nature of the adaptive immune response can clearly determine whether a virus infection is cleared or causes damage to the host. However, an uncontrolled or inappropriate adaptive response can also be damaging. A complete understanding of how viruses cause cause disease requires an appreciation of the adaptive immune response, a subject we’ll take on over the coming weeks.