This article was first printed in the Special Health Report from Harvard Medical School "The Truth about Your Immune System: What You Need to Know." For more information or to order, please go to http://www.health.harvard.edu/YI.)

Looking ahead

These are exciting times for immunology. After many years of digging into what makes the immune system function, the work of the past couple of decades is now beginning to bear a rich harvest. And this crop of discovery will benefit the well-being of people of all ages and all nationalities.

Researchers look at the immune system in two related but different ways: first, to learn more about specific diseases, and second, to learn more about the basic elements of biology, such as how cells talk to one another. Certainly the function, or malfunction, of the immune system can be crucial to the onset and course of many diseases. Infectious and autoimmune diseases, allergies, asthma, and cancer are examples of current research areas. But because the immune system depends on clear communication signals, it’s an excellent model to study to understand how cells in the body communicate. And controlling cell signaling, together with manipulating genes, could have clinical applications down the line.

Understanding the immune system and teasing out its mysteries are vital to progress in the prevention and treatment of lethal infectious diseases, from the diarrheal diseases that annually kill an estimated four million to six million children worldwide to the influenza that leads to 30,600 deaths each year in the United States. The major immunological research breakthrough of has been understanding how the two arms of the immune system — innate and adaptive — talk to each other. Whereas scientists once considered innate and adaptive immunity as two different but occasionally interacting systems, they now know that the two systems are vitally interconnected. Good connections make for a formidable immune response. Much present-day immunological research focuses on what constitutes these good connections and if they can be co-opted to amplify the warning “voice” so the ensuing response will be even greater.

Cell communication

Dendritic cells, those cells that present antigens to the T cells thereby firing up the immune response, have been the focus of much research. Similarly, researchers have homed in on the other half of the connection, the receptors on the surface of B and T cells, to understand how messages are received and relayed. Not unlike how information travels across the Internet, microbial information is broken into small packages and routed through various servers or pathways before being delivered as a cogent message — a rallying call to arms. Any point during that relay routing system represents an opportunity to amplify the signal and ultimately beef up the immune response.

Researchers have also been figuring out how the various cells of the immune system, such as the different types of killer lymphocytes, carry out their assigned task of destroying infected, damaged, or cancerous cells. By discerning what makes immune system cells do their job well, scientists have also come to appreciate, on a molecular level, why an immune response goes haywire. Recognizing what causes an inappropriate response can lead to ways to treat inflammatory autoimmune and allergic diseases. As well as the cells themselves, current investigations involve other chemicals involved in the innate/adaptive signaling process, such as cytokines.

Tomorrow’s vaccines

Making a new vaccine is a challenge. Did you know that most of today’s common vaccines have been available for half a century or more? Following a lag of some years in new vaccine development, vaccines are now enjoying a growth spurt as a result of research breakthroughs and major public health concerns. Progress is being made for diseases for which vaccines are long overdue.

Diarrheal diseases. Vaccines for diarrheal diseases, are in clinical trials. If successful, they would go a long way to reducing the death rate of up to six million children per year from diarrheal disease in developing countries. Diarrheal vaccines also would protect travelers to developing countries. A vaccine for malaria remains elusive, although research is ongoing.

AIDS. Developing a preventive vaccine for HIV/AIDS has proved immensely difficult because the virus infects the T cells of the immune system itself. Plus there are many different strains of HIV, with each strain undergoing antigenic changes. One question facing public health officials is: How many people would an HIV vaccine ultimately protect? Initiatives are under way to answer this question.

Measles. Current vaccines have been highly successful at protecting against what were formerly deadly or disabling diseases. But some vaccines are not ideal. The measles vaccine, for instance, illustrates the shortcomings of a current vaccine. Although effective, the vaccine is limited. It can’t be given to infants less than six months old because they still may retain their mother’s antibodies to measles (see “Why children need vaccination”). The vaccine requires refrigeration within a certain temperature range — a difficult challenge in many developing countries. Meanwhile, measles rampages on worldwide, accounting for 30–40 million cases each year, which represents 50%–60% of the deaths WHO attributes to vaccine-preventable childhood diseases. Measles is also a major cause of blindness. Happily, research is under way on a measles vaccine that can be given to very young infants by inhalation, targeting the respiratory tract where the virus typically enters the body. The advantages of this mode of vaccine administration are several: The vaccine can be given by trained but nonmedical staff, which makes the vaccine more readily accessible. And it also sidesteps the problems injectable vaccines present (see “Dodging shots: Alternatives to injectable vaccines”).

Cancer. People tend to think of vaccines only as a way of preventing infectious disease. But scientists are now developing therapeutic vaccines. This is especially true in the area of cancer research. For some time now, cancer researchers have been excited by the possibility of stimulating the immune system to mount a successful response against cancerous cells that remain in the body following the conventional treatments of surgery, chemotherapy, and radiation. Currently there are many research projects under way investigating how to harness the resources of the immune system in the fight against cancer. If successful, cancer vaccines could be extremely beneficial in beating back aggressively recurring tumors or in treating tumors in hard-to-reach places. Even so, cancer vaccines will work only for those cancers the immune system is able to recognize (see “Cancer: Missed cues”). For cancers the immune system perceives as “self,” vaccination will not be effective.

Alzheimer’s. On another front, researchers are actively investigating a vaccine that could halt the progression of Alzheimer’s disease. This vaccine triggers an immune response to produce antibodies against the production of a substance called amyloid in the brain that plays a role in Alzheimer’s. Human trials were discontinued in 2003 because the vaccine caused some patients to develop neuroencephalitis, an inflammation of the brain. But some patients who received the vaccine showed significant improvement in mental abilities, prompting researchers to continue to work to develop a version of the vaccine that does not cause brain inflammation.

Children. Most of today’s vaccines come as “one size fits all.” But not everyone is the same. Children and the elderly have distinct needs. Children are difficult to immunize for two reasons. Initially, they are protected by their mother’s antibodies (see “Why children need vaccination”). When those maternal antibodies see the harmless fragment of germ in the vaccine, they have no idea it isn’t the real McCoy. They attack it, which neutralizes the effect of the vaccine, so the child won’t have the long-term protection afforded by the vaccine. At the same time, the child’s own immune system isn’t fully developed. However, early vaccines that stimulate innate immunity would be effective protection at an early age because the innate immune system develops earlier — and appears to remain robust for longer.

Older folks. For elderly people, the problem is that vaccines afford less protection, and the protection provided by vaccines earlier in life appears to wear off. Why this should happen is not yet clear. But at the very time in life they are becoming more susceptible to infections, the elderly become more difficult to vaccinate. With that said, however, it is important for older folks to get annual flu vaccination, which does provide some additional protection in this population.

Inducing immune tolerance to “self”

The NIAID has made research into immune tolerance a research priority. The immune system’s inability to distinguish self from nonself and to subsequently destroy cells of the body it’s meant to protect is the cause of many immune disorders, including autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, type 1 diabetes, allergies, and asthma. One goal of this research is to understand how to help the immune system make the distinction between self and nonself. Investigating the genetic basis of autoimmunity also will point to new avenues of control. Also, as transplantation increases as a medical option, understanding how to induce tolerance will address the problem of long-term rejection of a transplanted organ, which occurs over time and can result in the need for a second transplant.