COMMENTARY Immunology research: challenges and opportunities in a time of budgetary constraint Charles J Hackett, Daniel Rotrosen, Hugh Auchincloss & Anthony S Fauci There have been enormous advances in the field of immunology over the past 3 decades, and those advances have had a positive effect on many subspecialties of medicine. Opportunities for even more notable advances remain. http://www.nature.com/natureimmunology However, present and projected budget constraints for the National Institutes of Health have created formidable challenges. This commentary addresses the opportunities and challenges for the field of immunology during a period of restricted budgets. any of the world’s major diseases— the 27 NIH institutes and centers fund research $3.7B $4.4B Minfection, cancer, autoimmunity and and training grants on immunology, attesting allergy—critically involve the immune system. to the fundamental importance of immuno- $1.6B Continued progress in understanding basic logy to every main disease area. In the NIH, $944M immune mechanisms is essential for developing the National Institute of Allergy and Infectious $406M $646M Nature Publishing Group Group Nature Publishing new abilities to treat and prevent diseases that Diseases (NIAID) oversees the largest portion 7 affect millions worldwide. Although federal of research on basic immunology and immune 1999 2003 2005 200 support for biomedical research has increased responses related to infectious and immune- Fiscal year © considerably over the past decade, funding has mediated diseases. Over the past decade, the Figure 1 Spending on immunology has continued remained flat over the past 3 years, leading to a NIH overall budget has grown considerably, to grow considerably along with the overall budget decrease in ‘purchasing power’ in the face of a increasing from $11.9 billion in fiscal year of the NIAID. As the NIAID budget increased from biomedical research inflation of approximately (FY) 1996 to $28.5 billion in FY 2005. In the $1.6 billion ($1.6B) in FY 1999 to $4.4B in FY 3%. Those budgetary constraints arrive at a same interval, the NIAID budget has grown at 2005, the spending on immunology (red disc; M, time of progress and excitement in the field an even faster pace, making NIAID the second million) also more than doubled. of immunology. This commentary addresses largest NIH institute, with an overall budget certain select opportunities for immunology of $4.4 billion. research, along with the challenges of imple- At present, the NIAID appropriation falls immunology research. Given the importance menting a robust immunology research agenda into three approximately equal categories of the science of immunology to biodefense, in an era of fiscal constraint. aligned with the institute’s main mission areas: HIV-AIDS and other infectious diseases, the human immunodeficiency virus (HIV) and investment by NIAID in immunology research The role of the NIH AIDS; biodefense; and immunology and infec- has the potential to grow considerably. Substantial but by no means the only support tious diseases, a category that includes research for immunology research comes from the on basic immunology, immune-mediated dis- Investigator-initiated research National Institutes of Health (NIH). Most of eases, microbiology, and infectious diseases Advances in fundamental immunology remind not in the HIV-AIDS or biodefense categories. us that the most important breakthroughs Although most immunology research has tra- in biomedical science generally have been Charles J. Hackett, Daniel Rotrosen, Hugh ditionally been supported by the appropriation achieved through the open-ended enquiry Auchincloss and Anthony S. Fauci are with the for immunology and infectious diseases, the that is the hallmark of investigator-initiated National Institute of Allergy and Infectious Diseases, discipline of immunology has also received research. Basic immunology research also pro- National Institutes of Health, Department of Health support from HIV-AIDS and biodefense vides the critical discoveries and mechanistic and Human Services, Bethesda, Maryland 20892, appropriations (Fig. 1). In FY 2005, the latest insights to underpin targeted programs that USA. year for which final figures are available, the address a growing expectation on the part of e-mail: [email protected] NIAID allocated more than $940 million to the administration, Congress and the general 114 VOLUME 8 NUMBER 2 FEBRUARY 2007 NATURE IMMUNOLOGY COMMENTARY public for concrete health-related advances in almost any biological molecule5. Harnessing molecules and antigen presentation mediated the form of ‘deliverables’,or products that can new knowledge about immune system func- by major histocompatibility complex class II be used to diagnose, prevent or treat disease.A tion is leading to ever-increasing capabilities molecules. Based on those principles, a grow- more detailed breakdown of NIAID spending to prevent or treat immune-mediated and ing list of adjuvant candidates now promises shows that growth in immunology research infectious diseases. However, even the consid- to provide improved vaccine immunogenicity occurred in several funding categories, with erable capacity of the immune system can be and reduced nonspecific reactivity while taking the largest continuing to be investigator-ini- overwhelmed by organisms naturally adapted advantage of the ability of the innate immune tiated research, which includes grants such as for virulence and immune evasion. For exam- system to channel adaptive immunity toward the individual R01, the exploratory or develop- ple, poxviruses, which include the smallpox the type of antibody or cellular responses most mental R21, small R03 and 1-year R56 bridge agent Variola major, may devote as many as appropriate for the control of a particular awards. Together these grants account for one half of their genes to virus-host interac- pathogen15. about 70% of all NIAID immunology research tions6. Understanding of the complexities of Immune tolerance holds the key to control- spending. Historically, solicited and unsolic- the scope of interactions between microbes and ling unwanted immunological attacks on self ited research programs typically have grown the immune system is just beginning. and transplanted tissues.Alloreactive responses in line with the overall budgetary growth of Although innate immunity is the most to transplanted tissues and organs have long the institute, with occasional deviations from ancient form of host defense, it is a key area been recognized as among the most powerful that general trend to address the urgent needs of discovery in contemporary immunology. known in immunology, being at least 100-fold of emerging research areas or the requirements The first ‘cluster of differentiation’ molecule, greater than those elicited by conventional for advanced development of medical coun- CD1, was identified in 1979 (ref. 7); however, antigens; such responses require potent, non- termeasures such as diagnostics, vaccines and more than 15 years passed before its function specific immunosuppression to maintain organ therapeutics. For example, solicited research as as a lipid antigen-presenting molecule in both allografts in clinical practice. In contrast, auto- a fraction of the NIAID immunology research innate and adaptive immunity was estab- immune diseases involve the loss of tolerance portfolio grew from about 20% in FY 1999 to lished8.At present,the field of innate immunity to self antigens. The identification of genes http://www.nature.com/natureimmunology about 30% in FY 2005, due mainly to biode- is moving rapidly and is providing the molec- involved in the establishment and maintenance fense contracts. ular basis for addressing decades-old ques- of central and peripheral tolerance provides a Nonetheless, we remain steadfastly con- tions concerning host defense mechanisms. new level of understanding and, potentially, vinced that it is the ingenuity of individual For example, although the function of type 1 control of deleterious immune responses. For scientists, expressed through investigator-ini- interferon responses to viral infection has been example, induction of central T cell tolerance tiated research, that will drive future discovery appreciated since 1957 (ref. 9), understanding is promoted by thymic expression of periph- in immunology, as in most areas of biomedical of the triggering of interferon synthesis was ill eral antigens related to the function of the gene science. That principle is broadly supported in defined until studies showed it to be based, for encoding the transcription factor Aire16. In the the scientific community, as demonstrated by many viruses, on cellular recognition of viral peripheral tissues, active antigen-specific sup- editorials and commentaries in the scientific single-stranded or double-stranded RNA. The pression mediated by a variety of T cells has 1 Nature Publishing Group Group Nature Publishing press and by the recommendations of many innate immune system casts a wide net for been repeatedly and reliably observed over 7 focus groups and expert panels convened by viral RNA, including the endosomal recep- decades. The association of the gene encoding 200 the NIAID (http://www.niaid.nih.gov/pub- tors TLR3 (which recognizes double-stranded the transcription factor Foxp3 with immune © lications/). Such discussions, including our RNA) and TLR7 and TLR8 (which recognize disorders and the linking of that gene to regula- ongoing dialog with academic and