PERSPECTIVE
Could Asthma Be Worsened by Stimulating the T-helper Type 1 Immune Response?

Mario Castro, David D. Chaplin, Michael J. Walter, and Michael J. Holtzman

Departments of Medicine and Cell Biology, Washington University School of Medicine; and the Howard Hughes Medical Institute, St. Louis, Missouri

The "Th2 hypothesis" for asthma pathogenesis is based on a relative increase in T-helper (Th) type 2 (Th2) cellular responses in combination with a decrease in Th1 re- sponses. The consequent alteration in cytokine milieu (most likely in the lung), with excess Th2 products (e.g., interleukin [IL]-4, IL-5, and IL-13) in concert with decreased Th1 products (e.g., interferon [IFN]- and IL-12), is predicted to drive the asthma phenotype. Evidence for such a shift in the Th1/Th2 balance derives from studies of asthma in cellular and murine models, where Th cell polarization and allergen-dependence of Th2 responses are most easily defined (1), and from human studies that profile cytokine production (2, 3). As noted previously (4) and again herein, this paradigm may be challenged, but even if correct, the basis for its development (and a consequent strategy to prevent it) remains uncertain.

A leading proposal to explain the imbalance toward Th2 responses (and the asthma epidemic) is that developmental stimuli of the Th1 system are lacking in the present compared with past eras. If so, it then becomes natural to propose that increased stimulation of the Th1 system, presumably early in life and selective for the lung, may serve to prevent the Th2 diathesis and resulting atopic diseases such as asthma. All of these possibilities are cogently espoused in the accompanying perspective by von Hertzen and Haahtela (5) as well as other recent reports (6). In the current case, the authors combine this point of view with the related need for an improved vaccine for another pressing health problem, i.e., tuberculosis. In combination, they suggest that early life induction of a Th1 immune response by vaccination with a better Calmette-Guerin bacillus (BCG) (or other species of Mycobacteria), if strong enough to evoke immune memory, may prevent environmental sensitization to allergens and the development of a Th2-dependent disease such as asthma. In this perspective, we aim to point out some of the "other" issues related to this proposal; first in relation to the development of the immune phenotype, and second, to what happens after the phenotype is developed (e.g., during a flare of the disease).

	Development of Adaptive Immunity

As we contemplate manipulating the immune repertoire by childhood vaccination, it may be useful to recall that the development of the immune phenotype of an individual appears to start in utero. T-cell priming is already evident at birth and shows a Th2 bias (9). Whether this reflects a default pathway or a programmed attempt to diminish toxic effects of IFN- is uncertain. In any case, the nonatopic normal infant then goes on to rapidly develop a Th1 response (with increased capacity for IFN- production) and so presumably extinguishes the predominant Th2 phenotype that was present at birth. In contrast, the atopic infant exhibits slower development of IFN-- producing cells and so may allow for persistence and further expression of the Th2 phenotype. The basis for this difference in Th1 development is uncertain, inasmuch as the status of antigen-presenting cells, IL-12, IL-12 receptor, IL-18, or other T-cell differentiation factors remains incompletely defined. Nonetheless, a prevailing view is that the infant's change in Th phenotype may reflect environmental experiences during the first year or two of life (10). In fact, ongoing studies in our group and others (initiated by a National Institutes of Health program on early childhood factors in asthma) are more definitively addressing this issue. These studies are following the fate of infants in regard to phenotype and genotype issues for cytokine production and signaling, experience with respiratory viral infection, and the development of atopy and asthma. The results may therefore more conclusively assign the circumstances for developing atopic disease.

While these chicken/egg issues are being defined, some clues about immune-cell (especially T-cell) behavior are already present from previous studies of infections and asthma (especially during childhood). Unfortunately, results do not yet provide a clear picture of the consequences of microbial contact. In the case of respiratory viruses, some have demonstrated that infection protected against the development of a Th2 phenotype and atopy (11, 12). However, others suggested that the risk of asthma increases with the number of infections in a child (13). At least part of the differences rests on the likelihood that the type of infection (in terms of the agent and the host) may influence immune events. In that regard, it appears that respiratory syncytial virus (RSV), the vector most closely linked to the development of childhood asthma, may be unusually associated with a Th2 response in infants (14) and in experimental models (15, 16). In studies of humans, however, it is difficult to exclude a bias for selecting infants who were predisposed to bronchiolitis (the clearest risk factor for subsequent asthma) by antecedent Th status (17). In a recent prospective study, susceptibility to RSV bronchiolitis and subsequent childhood wheezing was unrelated to subsequent atopy (18), but how this cohort of children behaves in later years and how their behavior relates to T-cell phenotype is still uncertain. The chicken and the egg therefore remain inseparable.

A similarly uncertain picture for immunomodulation emerges for consequences of tuberculous infection. A survey of schoolchildren indicated an inverse association between tuberculin responses and atopic disorders, so a positive response predicted a lower incidence of asthma, lower serum immunoglobulin E levels, and a bias toward a Th1 phenotype (6). At the same time, another retrospective study indicated that early BCG vaccination was not protective from developing asthma or atopy (19). These differences may be resolved by proposing that natural infections but not weaker responses to vaccination are protective against atopic disease. Mouse models of asthma support this point of view, but these studies (as noted later) use mature mice and so target a relatively mature immune system (20). In fact, none of these studies directly assess the consequences of early tuberculosis (or any other infection, vaccination, or immune stimulus) on the development of the immune phenotype. Consequently, whether or not immunoregulation of primed cells (or more likely differentiation of uncommitted T cells) to a Th1 phenotype is effective in altering the ultimate balance of Th phenotypes and/ or suppressing the Th2 phenotype is uncertain. A skewed Th2-type profile in asthma may also reflect a defect in T-cell apoptosis because T cells from asthmatics may be in an environment where the Fas system is less active and so may preferentially eliminate the more susceptible Th1 cells (21). All of these possibilities need to be defined in order to advocate vaccination to prevent asthma, especially because Th1 stimulation may lead to other immune problems. An obvious problem is the linkage between increased Th1 responses and autoimmune disease (22), but it also remains possible (as outlined later) that the Th1 immune axis may itself contribute to the asthmatic condition.

	Clues from the Innate Immune System

Before proceeding to further lessons from the T cell, we also point out that the T cell (and other components of the adaptive immune system) gets critical clues for behavior from the innate system (23). In that regard, we are beginning to learn about asthma pathogenesis from the behavior of the innate immune system. Thus, contributions by "uneducated" immune cells (e.g., natural killer [NK] cells) may be required for allergen responses (24), but nonimmune cells may also regulate the host response to allergen and to respiratory pathogens. Airway epithelial cells appear specially programmed for host defense by expression of a subset of immune-response genes, and this same subset appears to be abnormally activated in asthma (25). In stable asthma, the pattern of activation exhibits features of a Th1 response because the marker of activation (the signal transducer and activator of transcription [Stat]1 transcription factor) normally mediates actions of IFN- (26). Initial work indicates that the system may even be primed for further overshoot, e.g., by overexpression of Stat1 (27). In flares of the disease, additional epithelial gene networks are activated that may also contribute to a Th1 response (28, 29). Together, these abnormalities indicate that components of the Th1 milieu may be enhanced (rather than diminished) in asthma, even without evidence of stimuli (such as IFN- or productive viral infection) that normally drive this type of immune reaction. This defensive programming, at least part of which is innate, provides critical direction to the adaptive immune response. Whether additional Th1 stimulation by mycobacterial infection, attenuated viruses, other microbial stimuli (notably generic CpG oligodeoxynucleotides and specific DNA vaccines) or IL-12 might push this system further in the "wrong" direction remains a possibility.

The possibility that at least some Th1 stimuli may augment the asthmatic phenotype also appears demonstrable in experimental models of asthma. Thus, in addition to a well-described role for respiratory viral infections in causing exacerbations of "mature" asthma (see later discussion), it appears that respiratory viruses may have a primary role in initiating the disease. Studies using mice, rats, and guinea pigs have all demonstrated that a single primary infection with RSV or Sendai virus (another member of the Paramyxovirus family) can cause profound airway remodeling and concomitant increases in airway reactivity (30). Further, these pathophysiologic alterations can persist for at least a year (or nearly a lifetime in a mouse) after a single viral infection (or in broader terms, a single Th1 stimulation). At present, the mechanism for these effects and their consequent linkage to other Th1 stimuli, alterations in Th cell phenotype, and atopic disease is still under study. Meanwhile, however, the data provide the basis for at least some pause to question the outcome for how natural or artificial Th1 stimuli might interact with the underlying asthmatic genotype in human subjects, especially children.

	Ongoing Battles of More Mature Immunity

In addition to modulation of immune (and airway) development, potent Th1 stimulation may also modulate the more mature (effector) immune response to allergens. In fact, advocacy of Th1 stimulation to prevent atopic disease stems mainly from studies that modulate a relatively established system (the likely situation for therapy of asthma). Thus, it was critical that studies of mature mice indicated that infection with Mycobacterium bovis-BCG or treatment with IFN-, IL-12, or CpG oligonucleotides dampened Th2-dependent responses not only to initial allergen sensitization but also to subsequent allergen challenge (7, 8, 20, 33, 34). Efficacy may involve B cell, macrophage, dendritic cell, and/or NK cell activation, and at least in part, generation of IL-12 and IFN-, but the basis for effectiveness remains uncertain because effects may persist in mice deficient in these cytokines. In this case (as in others), generation of IL-6 and/or tumor necrosis factor (TNF)- may also contribute to efficacy (22). Understanding the basis for an anti-allergic effect begs for better definition inasmuch as portions of this same immune axis may be activated as a part of the asthma phenotype. Similarly, whether Th1 stimulation during the sensitization phase will translate short- or long-term into modifying immune phenotype and the subsequent development of atopic disease in human subjects remains uncertain. These questions can be approached by studying Th1 stimuli in experimental models of asthma, e.g., in mice. Extrapolation of these systems to vaccination in early childhood will require consideration of the maturity and plasticity of the T-cell phenotype as well as the underlying genotype.

Studies on immune development may also require further studies of the effector stage of the immune response. In particular, the proposed use of Th1 stimuli for asthma treatment must somehow also reconcile the age-old clinical and experimental saw that (as noted earlier) respiratory viral infections may trigger flares of the disease. In fact, acute models indicate that viral infection leads to an increase in the Th2-dependent response to allergen (35- 37). In the case of RSV, this may depend on its unusual capacity (at least under some circumstances) to trigger Th2 responses that would add to the asthma phenotype (14- 17). However, other well-defined model systems indicate that the usual Th1 stimulation may also contribute to worsening Th2-dependent responses. Thus, in immunodeficient or wild-type mouse models of asthma, it appears that the asthma phenotype conferred by passive transfer of ovalbumin-specific Th2 cells was not downregulated by the addition of stimulated Th1 cells (38). Failed blockade was apparent whether Th1 cells were given during allergen sensitization or challenge. In fact, with short sensitization and transfer phases in immunocompetent mice designed to better exclude a contribution of endogenous immune cells, the transferred Th1 cells may synergize with Th2 cells to promote allergen-induced tissue eosinophilia (D. Randolph and coworkers, submitted manuscript). The capacity of Th1 (but not Th2) cells to primarily respond to allergen may be based on their superior capacity to circulate into tissue (41, 42). The consequent Th1-dependent increase in cytokine (TNF-) production and vascular cell adhesion molecule (VCAM-1) expression in the airway then allows for Th2-dependent inflammation. This modified (and more traditional) scheme for Th1/Th2 interaction are summarized in Figure 1. Depending on the experimental (and clinical) conditions and the underlying genotype, it is therefore possible that Th1 stimulation (by viral or other means) may increase rather than dampen the Th2 response and so lead to more profound eosinophilic inflammation.

View larger version (32K): [in this window] [in a new window]   Figure 1.   Schematic diagram illustrating the role of the airway immune response in the development of asthmatic airway inflammation. Panel a illustrates how decreases in virus-driven production of Th1 cytokines (e.g., IFN-) and increases in allergen-dependent production of Th2 cytokines (e.g., IL-4) are characteristic of asthma (A). This Th2-skewed setting thereby provides for flares of the disease driven either by virus infection (with a functional blockade in the normal Th1 response and a concomitant shift to an increase in the Th2 response) or by allergen (with an increase in the Th2 response). Panel b illustrates a modified scheme based on an increased activity of both Th1 and Th2 responses. In this case, pathogen-activated Th1 cells in the airway tissue generate factors (e.g., TNF-) that mediate subsequent recruitment of Th2 cells (e.g., via VCAM-1) that provide a setting for enhanced allergen responsiveness.

	Summary

In summary, von Hertzen and Haahtela (5) propose the interesting idea of aiming at two birds with one immunologic stone: an improved vaccine for tuberculosis that may also generically boost the Th1 immune response and so prevent the Th2  Th1 phenotype that "causes" atopy. While we recognize that there is potential efficacy in this approach, we also present the view that immunomodulation in early life (or later in life as therapy) should be carefully studied before proceeding with efforts to artificially stimulate the Th1 response. In regard to immune development, we note a paucity of evidence that indicates immune stimulation will alter the organism's Th phenotype or whether an alteration in Th phenotype will modify the development of atopic disease. In regard to modifying the more mature immune response (i.e., targeting the effector response), we note that asthma pathogenesis may include activation of Th1 pathways as well as allergen-driven overproduction of Th2-type cytokines. Thus, amplification of either side of the Th1/Th2 balance may be adverse to the host. Perhaps future efforts at preventing the development of atopic disease in early life might better focus on more completely defining the basis for immune phenotype and so more precisely and subtly prevent airway inflammation without compromising airway immunity.

	Footnotes

Address correspondence to: M. Castro, Washington University School of Medicine, Campus Box 8052, 660 S. Euclid Ave., St. Louis, MO, 63110. E-mail: mcastro{at}im.wustl.edu

(Received in original form September 14, 1999).

	References

1. Cohn, L., J. S. Tepper, and K. Bottomly. 1998. IL-4-independent induction of airway hyperresponsiveness by Th2, but not Th1, cells. J. Immunol. 161: 3813-3816 [Abstract/Free Full Text].

2. Ying, S., S. R. Durham, C. J. Corrigan, Q. Hamid, and A. B. Kay. 1995. Phenotype of cells expressing mRNA for TH2-type (interleukin 4 and interleukin 5) and TH1-type (interleukin 2 and interferon ) cytokines in bronchoalveolar lavage and bronchial biopsies from atopic asthmatic and normal control subjects. Am. J. Respir. Cell Mol. Biol. 12: 477-487 [Abstract].

3. Nakamura, Y., O. Ghaffar, R. Olivenstein, R. A. Taha, A. Soussi-Gounni, D.-H. Zhang, A. Ray, and Q. Hamid. 1999. Gene expression of the GATA-3 transcription factor is increased in atopic asthma. J. Allergy Clin. Immunol. 103: 215-222 [Medline].

4. Holtzman, M. J., D. Sampath, M. Castro, D. C. Look, and S. Jayaraman. 1996. The one-two of T helper cells: does interferon- knock out the Th2 hypothesis for asthma? Am. J. Respir. Cell Mol. Biol. 14: 316-318 [Medline].

5. von Hertzen, L. C., and T. Haahtela. 2000. Could the risk of asthma and atopy be reduced by a vaccine that induces a strong T helper type 1 response? Am. J. Respir. Cell Mol. Biol. 22: 139-142 [Free Full Text].

6. Shirakawa, T., T. Enomoto, S. Shimazu, and J. M. Hopkin. 1997. The inverse association between tuberculin responses and atopic disorders. Science 275: 77-79 [Abstract/Free Full Text].

7. Kline, J. N., T. J. Waldschmidt, T. R. Businga, J. E. Lemish, J. V. Weinstock, P. S. Thorne, and A. M. Krieg. 1998. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J. Immunol. 160: 2555-2559 [Abstract/Free Full Text].

8. Broide, D., J. Schwarze, H. Tighe, T. Gifford, M.-D. Nguyen, S. Malek, J. Van Uden, E. Martin-Orozco, E. W. Gelfand, and E. Raz. 1998. Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice. J. Immunol. 161: 7054-7062 [Abstract/Free Full Text].

9. Prescott, S., D. Macaubas, T. Smallacombe, B. Holt, P. Sly, and P. Holt. 1999. Development of allergen-specific T-cell memory in atopic and normal children. Lancet 353: 196-200 [Medline].

10. Holt, P. G.. 1996. Primary allergic sensitization to environmental antigens: perinatal T cell priming as a determinant of responder phenotype in adulthood. J. Exp. Med. 183: 1297-1301 [Free Full Text].

11. Shaheen, S. O., P. Aaby, A. J. Hall, D. J. P. Barker, C. B. Heyes, A. W. Shiell, and A. Goudiaby. 1996. Measles and atopy in Guinea-Bissau. Lancet 347: 1792-1796 [Medline].

12. Matricardi, P. M., F. Rosmini, L. Ferrigno, R. Nisini, M. Rapicetta, P. Chionne, T. Stroffolini, P. Pasquini, and R. D'Amelio. 1997. Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. Br. Med. J. 314: 999-1003 [Abstract/Free Full Text].

13. Bodner, C., D. Godden, and A. Seaton. 1999. Family size, childhood infections and atopic diseases. Thorax 53: 28-32 [Abstract].

14. Roman, M., W. J. Calhoun, K. L. Hinton, L. F. Avendano, V. Simon, A. M. Escobar, A. Gaggero, and P. V. Diaz. 1997. Respiratory syncytial virus infection in infants is associated with predominant Th-2-like response. Am. J. Respir. Crit. Care Med. 156: 190-195 [Abstract/Free Full Text].

15. Srikiatkhachorn, A., and T. J. Braciale. 1997. Virus-specific CD8⁺ T lymphocytes downregulate T helper cell type 2 cytokine secretion and pulmonary eosinophila during experimental murine respiratory syncytial virus infection. J. Exp. Med. 186: 421-432 [Abstract/Free Full Text].

16. Tebbey, P. W., M. Hagen, and G. E. Hancock. 1998. Atypical pulmonary eosinophilia is mediated by a specific amino acid sequence of the attachment (G) protein of respiratory syncytial virus. J. Exp. Med. 188: 1967-1972 [Abstract/Free Full Text].

17. Renzi, P. M., J. P. Turgeon, J. E. Marcotte, S. P. Drblik, D. Berube, M. F. Gagnon, and S. Spier. 1999. Reduced interferon- production in infants with bronchiolitis and asthma. Am. J. Respir. Crit. Care Med. 159: 1417-1422 [Abstract/Free Full Text].

18. Stein, R. T., D. Sherrill, W. J. Morgan, C. J. Holberg, M. Halonen, L. M. Taussig, A. L. Wright, and F. D. Martinez. 1999. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 345: 541-545 .

19. Alm, J., G. Lilja, G. Pershagen, and A. Scheynius. 1997. Early BCG vaccination and development of atopy. Lancet 350: 400-403 [Medline].

20. Erb, K., J. Holloway, A. Sobeck, H. Moll, and G. Le Gros. 1998. Infection of mice with Mycobacterium bovis-Bacillus-Calmette-Guerin (BCG) suppresses allergen-induced airway eosinophilia. J. Exp. Med. 187: 561-569 [Abstract/Free Full Text].

21. Jayaraman, S., M. Castro, M. O'Sullivan, M. J. Bragdon, and M. J. Holtzman. 1999. Resistance to Fas-mediated T cell apoptosis in asthma. J. Immunol. 162: 1717-1722 [Abstract/Free Full Text].

22. Klinman, D. M., D. Verthelyi, F. Takeshita, and K. J. Ishii. 1999. Immune recognition of foreign DNA: a cure for bioterrorism. Immunity 11: 123-129 [Medline].

23. Medzhitov, R., and C. A. Janeway Jr.. 1998. An ancient system of host defense. Curr. Opin. Immunol. 10: 12-15 [Medline].

24. Korsgren, M., C. G. A. Persson, F. Sundler, T. Bjerke, T. Hansson, B. J. Chambers, S. Hong, L. Van Kaer, H.-G. Ljunggren, and O. Korsgren. 1999. Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice. J. Exp. Med. 189: 553-562 [Abstract/Free Full Text].

25. Holtzman, M. J., D. C. Look, D. Sampath, M. Castro, T. Koga, and M. J. Walter. 1998. Control of epithelial immune-response genes and implications for airway immunity and inflammation. Proc. Assoc. Am. Phys. 110: 1-11 . [Medline]

26. Sampath, D., M. Castro, D. C. Look, and M. J. Holtzman. 1999. Constitutive activation of an epithelial signal transducer and activator of transcription (Stat1) pathway in asthma. J. Clin. Invest. 103: 1353-1361 [Medline].

27. Sampath, D., W. T. Roswit, T. Koga, M. J. Walter, D. C. Look, M. Castro, and M. J. Holtzman. 1998. Autoamplification of Stat1-dependent gene expression. FASEB J. 12: A1390 .

28. Taguchi, M., D. Sampath, T. Koga, M. Castro, D. C. Look, S. Nakajima, and M. J. Holtzman. 1998. Patterns for RANTES secretion and intercellular adhesion molecule-1 expression mediate transepithelial T cell traffic based on analyses in vitro and in vivo. J. Exp. Med. 187: 1927-1940 [Abstract/Free Full Text].

29. Siveke, J. T., and A. Hamann. 1998. T helper 1 and T helper 2 cells respond differentially to chemokines. J. Immunol. 160: 550-554 [Abstract/Free Full Text].

30. Kumar, A., R. L. Sorkness, M. R. Kaplan, and R. F. J. Lemanske. 1997. Chronic, episodic, reversible airway obstruction after viral bronchiolitis in rats. Am. J. Respir. Crit. Care Med. 155: 130-134 [Abstract].

31. Riedel, F., B. Oberdieck, H.-J. Streckert, S. Philippou, T. Krusat, and W. Marek. 1997. Persistence of airway hyperresponsiveness and viral antigen following respiratory syncytial virus bronchiolitis in young guinea pigs. Eur. Respir. J. 10: 639-645 [Abstract].

32. Walter, M. J., N. Kajiwara, D. Xia, and M. J. Holtzman. 1999. Early-phase innate immunity and late-phase remodeling of the epithelium during primary viral bronchitis and hyprreactivity. J. Invest. Med. 47: 256A .

33. Lack, G., K. L. Bradley, E. Hamelmann, H. Renz, J. Loader, D. Y. M. Leung, G. L. Larsen, and E. W. Gelfand. 1996. Nebulized IFN- inhibits the development of secondary allergic responses in mice. J. Immunol. 157: 1432-1439 [Abstract].

34. Gavett, S. H., D. J. O'Hearn, X. Li, S.-K. Huang, F. D. Finkelman, and M. Wills-Karp. 1995. Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice. J. Exp. Med. 182: 1527-1536 [Abstract/Free Full Text].

35. Lemanske, R. F. Jr., E. C. Dick, C. A. Swenson, R. F. Vrtis, and W. W. Busse. 1989. Rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions. J. Clin. Invest. 83: 1-10 .

36. Riedel, R., A. Krause, W. Slenczka, and C. Rieger. 1996. Parainfluenza-3-virus infection enhances allergic sensitization in the guinea pig. Clin. Exp. Allergy 26: 603-609 [Medline].

37. Schwarze, J., E. Hamelmann, K. L. Bradley, K. Takeda, and E. W. Gelfand. 1997. Respiratory syncytial virus infection results in airway hyperresponsiveness and enhanced airway sensitization to allergen. J. Clin. Invest. 100::226-233.

38. Li, L., Y. Xia, A. Nguyen, L. Feng, and D. Lo. 1998. Th2-induced eotaxin expression and eosinophilia coexist with Th2 responses at the effector stage of lung inflammation. J. Immunol. 161: 3128-3135 [Abstract/Free Full Text].

39. Hansen, G., G. Berry, R. DeKruyff, and D. Umetsu. 1999. Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J. Clin. Invest. 103: 175-183 [Medline].

40. Randolph, D. A., C. J. L. Carruthers, S. J. Szabo, K. M. Murphy, and D. D. Chaplin. 1999. Modulation of airway inflammation by passive transfer of allergen-specific Th1 and Th2 cells in a mouse model of asthma. J. Immunol. 162: 2375-2383 [Abstract/Free Full Text].

41. Austrup, F., D. Vestweber, E. Borges, M. Lohning, R. Brauer, U. Herz, H. Renz, R. Hallmann, A. Scheffold, A. Radbruch, and A. Hamann. 1997. P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissues. Nature 385: 81-83 [Medline].

42. van Wely, C. A., P. C. L. Beverley, S. J. Brett, C. J. Britten, and J. P. Tite. 1999. Expression of L-selectin on Th1 cells is regulated by IL-12. J. Immunol. 163: 1214-1221 [Abstract/Free Full Text].