An Analysis of Reponses to the Immunology Questionnaire

The Science On-Line Immunology Questionnaire, first featured on 5 April 1996, focused on immunological therapies--that is, which approaches are considered most likely (and most unlikely) to become clinical realities, what are the chances of success of those that are introduced, and what are the likely time scales for their introduction. It did so for two reasons. First, the principal (but not sole) indicator of the value of immunological knowledge comes with its application to medicine. Second, although immunologists have a diverse range of expertise, we wanted to see if areas of agreement and disagreement could be revealed.

Although the survey simply reflects the opinions of the self-selected group of more than 100 individuals who participated, the findings nonetheless make for interesting reading. Among the strongly supported responses, there was a notable amount of agreement on the future importance of an integrated approach to the immune system and immune pathology, as well as confidence that new therapies, such as clinical transplantation tolerance and vaccines for malaria, will ultimately be developed. In other areas, such as tumor immunotherapy, there was no consensus yet on the best way forward.

The responses in Sections 1 and 2 are largely self-evident from the graphs. We highlighted points of interest to us in the discussion, which can perhaps serve as a basis for further discussion. For Section 3, the open response section, we summarize the major themes of the responses and touch upon some of the specific comments made.

We would be pleased to have reactions to any aspect of the questionnaire: If these responses are sent soon enough, we will consider posting them as an addendum to this report.

Our thanks to all those who participated in the creation of the questionnaire, responded to it, and gave technical support throughout the process.

Richard B. Gallagher, Linda J. Miller, Nigel Williams

Section 1

Reaction to a couple of the statements was unexpectedly diverse. For example, we would not have guessed that there would be such a range of responses to the idea that immunoregulation would control the progression of AIDS (Q23); our expectation was that this would be a well-supported concept. And the question of animal models as indicators of the success of therapies in human diseases (Q12) produced a surprisingly ambivalent response: many neither strongly agreed nor disagreed, when we would have predicted two quite definite camps, one supporting and one rejecting the statement. It is, of course, possible that a group of respondents felt that for some diseases current models are good indicators, whereas for others they are not, and thus voted for the middle ground.

Some of the statements that evoked the most clear-cut responses, either agreement or disagreement, also provided some mild surprise. For example, a large majority believe that molecular mimicry plays a key role in the initiation of the disease process (Q15)--clearly the concept is alive and well although the term is not seen as often today as it once was. And there was a strong feeling that new generations of immunosuppressive drugs are, by themselves, not the answer to the problems of immunological tolerance (Q17); despite the success of the current crop of drugs in transplantation settings and despite further generations on the way, the community still sees a central role for antigen-specific mechanisms.

The importance of understanding genetic predisposition to disease was acknowledged, but subtly different responses were given to two questions on the topic. Most respondents agreed that the search for the genetic basis of autoimmune disease was at least as crucial as learning to manipulate the response (Q8). However, in another question (Q16), the majority did not go along with the view that investigating the genetics of allergy would yield the best information for new treatments.

A pattern of sorts did emerge from the statements that dealt with cancer therapy (Q 1, 14, 18, 25): Unfortunately, the pattern was that the majority disagreed with the prime importance of any one particular therapy, be it tumor vaccines (Q 1, 14), the manipulation of costimulation (Q18), or adoptive T cell therapy (Q25). This lack of consensus does not, of course, bode ill for the field. In fact, it is consistent with the ongoing development of several promising approaches and with the view that combinations of approaches are most likely to bring success.

With regard to vaccine development, salutory caution was demonstrated in the responses to a couple of statements: a large number of respondents disagreed with the suggestions that oral vaccine delivery will replace parenteral administration within a decade (Q4) and that DNA vaccination negates the need for new adjuvants to be developed (Q24).

[Data] Graphs of results for questions 1 through 9

[Data] Graphs of results for questions 10 through 19

[Data] Graphs of results for questions 20 through 27

Section 2

Ranking the questions in this section in temporal order reveals an interesting sequence for the possible introduction of new therapeutic modalities. The introduction of new adjuvants was seen as likely to occur first, with almost everyone who expressed an opinion foreseeing this happening within the decade; half of these anticipate it within 5 years. This question, however, also had the highest percentage of "don't knows" (more than 30%). Responses to questions about the boosting of the immune system of HIV patients, the licensing of DNA vaccines, and the use of peptide antagonists also leaned toward seeing relatively early introduction, although there is a body of opinion that the first and (particularly) the third of these approaches are unlikely to be successfully developed. There was a notably wide spread of estimates for the introduction of islet xenotransplantation, whereas therapeutic use of cancer vaccines, tolerization both to transplants and in autoimmune disease, and the introduction of a malaria vaccine are seen as somewhat further off. Only a very small number of respondents viewed transplant tolerance and a malaria vaccine as being unlikely. The bad news for infectious disease treatment is that a substantial minority thought unlikely a cure of infectious diseases using cytokine therapy, and those that could foresee this happening set it as the most distant of the 10 developments.

[Data] Graphs of results for questions 1 through 10

Section 3

Q1. Although a 10th of the respondents characterized immunotherapy as immature, inadequate, or oversold, twice as many had a sense of optimism, noting that many advances have been made. Two out of every five responses pointed out how much remains to be learned: Among the topics highlighted for further study were the regulatory interactions among cell populations and in cytokine networks, immune memory, cell proliferation versus cell death decisions, and peripheral tolerance. Approaches considered to hold the most promise were based mostly on specific antigens or manipulation of antigen-specific clones. The potential barriers to progress that were mentioned included funding pressures [causing overemphasis on particular approaches (see Q2)], lack of controlled clinical trials, and technical difficulties associated with the scaling up of experimental approaches.

Q2. The majority (almost two-thirds) of respondents felt that the Th1/Th2 paradigm was useful to the development of immunotherapy, whereas a minor but nonetheless substantial group (more than one-third) felt that it was a hindrance. Those in favor thought it provided an extremely useful basis on which to frame important questions regarding therapy (several thought that it was the most useful); those against worried that it would result in too narrow a focus for therapeutic options. Those who thought it useful cited the very solid experimental basis of the Th1/Th2 duality, particularly from murine studies; those who thought it a hindrance often mentioned that there are worrisome discrepancies between mouse and human studies. Both groups agreed on one key point: that interpretation of pathology solely in terms of Th1 and Th2 responses would be a grave error. In almost all circumstances, pathogenic events will be considerably more complex.

Q3. This question was perhaps overly complex. Nevertheless, it did illustrate that there are almost as many viewpoints regarding the future paths for cancer immunotherapy as there are people willing to discuss this issue. Overall, the mood is somewhat pessimistic: three out of every 10 respondents felt universally negative about current progress and future prospects, whereas more than one-half agreed that approaches taken thus far had been disappointing. No consensus emerged on which approach is most likely to succeed in the future, with proponents for vaccines, dendritic cell-based therapies, use of T cell clones monoclonal antibodies, and cytokines all coming to the fore. Perhaps the single most notable feature of the responses was the rich crop of approaches that have yet to be fully assessed; this provides some reason for guarded optimism.

Q4. The question on xenotransplantation polarized opinion, with a majority of two to one asserting that xenotransplantation is a realistic goal. However, where stated, it was felt to be years off as a clinical treatment. The question also drew the most vehement negative reaction from respondents, as well as a long list, from both groups, of obstacles that will need to be overcome. In order of frequency cited, these obstacles are as follows: the dangers of zoonoses, inducing immune tolerance in the host, avoiding acute or hyperacute rejection of the transplanted organ, incompatibilities in metabolism, ethical dilemmas, financial burdens, and commercial secrecy.

Q5. Somewhat surprisingly, a solid list of topics that are considered to be underresearched emerged. Several of them shared a common feature: they dealt with immunity and immune pathology in an integrated fashion. Thus, psychoneuroimmunology was mentioned several times, and there were calls for a more "holistic approach" and for increased immunological surveillance. Perhaps this heralds the emergence of a new vigor in integrated immunology. Other topics that received "multiple hits" included mucosal immunology, cancer immunology, and parasitology.