Visceral Leishmania donovani Infection in Interleukin-13–/– Mice
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感染与免疫杂志 2006年第4期
Departments of Medicine Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021
ABSTRACT
Leishmania donovani-infected interleukin-13–/– BALB/c mice showed impaired initial gamma interferon secretion and incomplete granuloma assembly at parasitized liver foci. Nonetheless, control of early parasite replication, resolution of liver infection, and responsiveness to antileishmanial chemotherapy were intact. By itself, interleukin-13 does not appear to materially influence acquired resistance in this intracellular infection.
TEXT
In experimental visceral leishmaniasis, host defense against intracellular Leishmania donovani is T cell dependent and involves a range of T-cell- and macrophage-activating cytokines (15, 16, 25). In L. donovani infection in the liver, interleukin-12 (IL-12) and gamma interferon (IFN-) figure prominently in granuloma assembly, macrophage activation, and parasite killing, driving acquired resistance and eventual near resolution of infection (4, 12, 15, 16, 23, 26). In addition, the same inflammatory response supports the efficacy of conventional antileishmanial chemotherapy, pentavalent antimony (Sb) (15).
L. donovani infection also provokes expression of Th2-cell-type cytokines (IL-4, IL-10, and IL-13) and transforming growth factor (18), ordinarily considered counterbalancing, suppressive factors. These cytokines probably limit tissue injury but to various degrees also derail Th1-cell responses, deactivate macrophages, and promote infection (3, 9, 11, 17, 19, 27). In L. donovani-infected, susceptible, wild-type (WT) BALB/c mice, neutralization or receptor blockade has demonstrated a striking deactivating effect for IL-10, modest suppressive roles for transforming growth factor and IL-13, and no role for IL-4 (19). Nevertheless, studies with L. donovani-infected IL-4–/– BALB/c mice indicate a less well appreciated effect for IL-4 in supporting Th1-type responses and limiting initial liver parasite replication (1, 22, 25). In addition, susceptibility to L. donovani is further enhanced in IL-4 receptor -deficient (IL-4R–/–) BALB/c mice, in which higher liver parasite burdens correlated with deficient IFN- secretion and impaired granuloma maturation. Since IL-13 also signals via IL-4 receptor , a separate, similarly early-acting antileishmanial role was inferred for IL-13 (25).
To formally test the role of IL-13 alone, IL-13 gene-disrupted mice on a BALB/c background (5) were infected intravenously with 1.5 x 107 hamster spleen-derived L. donovani amastigotes (1 Sudan strain) (19). However, the course of infection in the liver, measured microscopically with tissue imprints and expressed as Leishman Donovan units (LDU) (19), proved nearly indistinguishable from the course of liver infection for WT BALB/c animals (Fig. 1). In particular, the level of infection was similar at week 4, the point at which liver parasite burdens in IL-4R–/– mice exceeded those in WT controls, before both groups resolved infection at week 8 (25).
Nevertheless, IL-13–/– mice showed defects in two linked expressions of Th1-cell-associated defense against L. donovani, IFN- secretion and granuloma assembly (15, 16). IFN- was measured in serum by enzyme-linked immunosorbent assay, and a value of 0 was arbitrarily assigned to results showing <31 pg/ml, the limit of detectability (19). IFN- was not detected in uninfected mice, and in two experiments, levels were lower at week 2 in IL-13–/– (15 ± 16 pg/ml) than in WT (56 ± 21 pg/ml) animals (mean ± standard error of the mean [SEM], n = 6 to 7 mice per group; P > 0.05). However, week 4 levels increased in IL-13–/– mice (140 ± 57 pg/ml), suggesting that reduction in IFN- secretion was transient. While measuring IFN- in serum is a useful marker of Th1-cell-type responses, the physiologic implication of activity in serum (versus in situ IFN- expression at the infected tissue focus) is unknown.
IL-13–/– mice also failed to generate the anticipated early cellular reaction at parasitized Kupffer cell foci at week 2 (Fig. 2B) (16). While granulomas formed by week 4, 85% were small and scored as developing (immature) (16), having attracted relatively few recruited mononuclear cells (Fig. 2D). Thus, at week 4, there was little evidence of transition to the mature-appearing, mononuclear-cell-rich structures (Fig. 2C) associated with control over L. donovani in WT mice (16, 25). Subsequent observations indicated no further progression towards granuloma maturation, as IL-13–/– mice showed involution of most granulomatous foci at week 8, with residual epithelioid changes similar to those in WT mice (Fig. 2E and F).
Since both IFN- and mononuclear cell recruitment regulate the leishmanicidal response to Sb chemotherapy within parasitized tissue (13, 14), we anticipated a deficient response to treatment for IL-13–/– mice. However, the efficacy of both optimal- and suboptimal-dose Sb (sodium stibogluconate [Pentostam]) (19) was preserved (Table 1). Suboptimal-dose Sb was used to test for more-subtle effects potentially induced by the absence of IL-13.
Together, our results suggest that IL-13 promotes initial IFN- production and show that IL-13 influences tissue granuloma assembly and maturation. However, these experiments have not addressed the mechanism(s) by which IL-13 regulates these two expressions of the antileishmanial Th1 response. Possibilities include that IL-13's effects, as reported for IL-4 (1, 24), support Th1-cell development (contributing to initial IFN- secretion) and shape subsequent responses, including granuloma maturation. Alternatively, although ordinarily considered a suppressive-type cytokine, IL-13 might also act to downregulate other deactivating mechanisms (e.g., IL-10 [7]) which limit initial IFN- secretion and restrain granuloma development.
Nevertheless, the absence of the two aforementioned effects in IL-13-deficient mice did not materially influence acquired resistance or eventual resolution of L. donovani infection in the liver. Similar results for IFN- and granulomatous responses have been demonstrated well for IL-4–/– and in a more pronounced fashion with IL-4R–/– BALB/c mice (25). However, and in contrast to our findings (Fig. 1), these same two effects correlated with increased initial susceptibility to L. donovani in both IL-4–/– and IL-4R–/– mice (25), possibly indicating a more primary role for IL-4 in supporting initial acquired resistance. Since IFN--induced macrophage activation and granuloma formation are clear-cut expressions of the Th1-cell-type response which controls liver infection in this model (16, 17, 19), our findings with IL-13–/– mice suggest an early-acting, compensatory, or IFN--independent mechanism. Such mechanisms may involve IL-12 and tumor necrosis factor (26) or IL-18 (20). Similarly, L. donovani-induced granuloma assembly can also proceed in an IFN--independent fashion (18, 26). Further, albeit under separate conditions (10), L. donovani infection can also be controlled in the absence of a granulomatous response.
These same IL-13–/– BALB/c mice as well as their C57BL/6 counterparts have also been tested with cutaneous L. major (5) and L. mexicana (2, 24) infection. These studies produced variable results for the role of IL-13, ranging from no role (24) to a protective (2) or a suppressive (2, 5) role. In IL-4R–/– mice, IL-13's inferred role in cutaneous infection has been similarly variable, depending upon the Leishmania strain tested (2, 8, 21). In our experiments, in which we used an L. donovani strain different from that tested with IL-4R–/– mice (25), the absence of IL-13 did not accelerate control of liver infection, enhance granuloma assembly, heighten IFN- secretion, or increase responsiveness to Sb chemotherapy-linked expressions of raised Th1-cell reactivity well expressed, for example, in IL-10–/– mice (17). Thus, IL-13 by itself does not appear to exert suppressive Th2-type cytokine effects in this model. Conversely, infection in IL-13–/– mice was not exacerbated, as would be anticipated (17, 19) if IL-13 played a meaningful prohost defense role. It is also worth pointing out that our observations are limited to the liver; thus, it is possible that different results might have been seen with the spleen, for example.
Nevertheless, endogenous IL-13 does have transient or limited effects in L. donovani infection but under quite different conditions: in conjunction with deficient IL-4 (e.g., in IL-4R–/– mice [26]), for intact WT mice injected with soluble IL-13 receptor 2 (IL-13R2) immunoglobulin G Fc (19), and for IL-13R2–/– mice (19). The effect of IL-13 again varies, however, depending upon the setting. BALB/c IL-4R–/– mice are initially more susceptible to L. donovani at week 4, suggesting an initially protective, albeit dispensable action for IL-13, since infection resolves normally by week 8 (26). Inhibition of IL-13 by IL-13R2 immunoglobulin G Fc treatment enhances inhibition of L. donovani replication in WT BALB/c mice but does not permit parasite killing (19). Finally, for IL-13R2–/– mice, which phenotypically resemble IL-13 transgenic animals (6), excess IL-13 suppresses IFN- secretion and granuloma assembly and promotes L. donovani infection; however, for IL-13R2–/– mice, the latter effect of IL-13 is also transient (19).
ACKNOWLEDGMENTS
This work was supported by NIH grants AI 16369 (H.W.M.) and AI 45899 (X.M.).
We are particularly grateful to A. Mackenzie for helping us acquire the IL-13–/– mice he developed.
REFERENCES
1. Alexander, J., K. C. Carter, N. Al-Fasi, A. Satoskar, and F. Brombacher. 2000. Endogenous IL-4 is necessary for effective drug therapy against visceral leishmaniasis. Eur. J. Immunol. 30:2935-2943.
2. Alexander, J., F. Brombacher, H. A. McGachy, A. N. McKenzie, W. Walker, and K. C. Carter. 2002. An essential role for IL-13 in maintaining a non-healing response following Leishmania mexicana infection. Eur. J. Immunol. 32:2923-2933.
3. deVries, J. E. 1998. The role of IL-13 and its receptor in allergy and inflammatory responses. J. Allergy Clin. Immunol. 102:165-169.
4. Engwerda, C. R., M. L. Murphy, S. E. Cotterell, S. C. Smelt, and P. M. Kaye. 1998. Neutralization of IL-12 demonstrates the existence of discrete organ-specific phases in the control of Leishmania donovani. Eur. J. Immunol. 28:669-680.
5. Matthews, D. J., C. L. Emson, G. J. McKenzie, H. E. Jolin, J. M. Blackwell, and A. N. J. McKenzie. 2000. IL-13 is a susceptibility factor for Leishmania major infection. J. Immunol. 164:1458-1462.
6. McKenzie, A. N. J., and P. G. Fallon. 2003. Decoy receptors in the regulation of T helper cell type 2 responses. J. Exp. Med. 197:675-679.
7. McKenzie, G. J., C. L. Emson, S. E. Bell, S. Anderson, P. Fallon, G. Zurawski, R. Murray, R. Grencis, and A. N. J. McKenzie. 1998. Impaired development of Th2 cells in IL-13-deficient mice. Immunity 9:423-432.
8. Mohrs, M., B. Ledermann, G. Khler, A. Dorfmüller, A. Gessner, and F. Brombacher. 1999. Differences between IL-4- and IL-4 receptor -deficient mice in chronic leishmaniasis reveal a protective role for IL-13 receptor signaling. J. Immunol. 162:7302-7308.
9. Murphy, M. L., U. Wille, E. N. Villegas, C. A. Hunter, and J. P. Farrell. 2001. IL-10 mediates susceptibility to Leishmania donovani infection. Eur. J. Immunol. 31:2848-2856.
10. Murray, H. W., K. E. Squires, C. D. Miralles, M. Y. Stoeckle, A. M. Granger, A. Granelli-Piperno, and C. Bogdan. 1992. Acquired resistance and granuloma formation in experimental visceral leishmaniasis: differential T cell and lymphokine roles in initial versus established immunity. J. Immunol. 148:1858-1865.
11. Murray, H. W., J. Hariprashad, and R. L. Coffman. 1997. Behavior of visceral Leishmania donovani in an experimentally-induced Th2 cell-associated response model. J. Exp. Med. 185:867-874.
12. Murray, H. W., C. Montelibano, R. Peterson, and J. P. Sypek. 2000. Interleukin 12 regulates the response to chemotherapy in experimental visceral leishmaniasis. J. Infect. Dis. 182:1497-1503.
13. Murray, H. W., and S. Delph-Etienne. 2000. Role of endogenous gamma interferon and macrophage microbicidal mechanisms in host response to chemotherapy in experimental visceral leishmaniasis. Infect. Immun. 68:288-293.
14. Murray, H. W. 2000. Mononuclear cell recruitment, granuloma assembly, and response to treatment in experimental visceral leishmaniasis: intracellular adhesion molecule 1-dependent and -independent regulation. Infect. Immun. 68:6294-6299.
15. Murray, H. W. 2001. Clinical and experimental advances in treatment in visceral leishmaniasis. Antimicrob. Agents Chemother. 45:2185-2197.
16. Murray, H. W. 2001. Tissue granuloma structure-function in experimental visceral leishmaniasis. Int. J. Exp. Pathol. 82:249-267.
17. Murray, H. W., C. M. Lu, S. Mauze, S. Freeman, A. L. Moreira, G. Kaplan, and R. L. Coffman. 2002. Interleukin-10 (IL-10) in experimental visceral leishmaniasis and IL-10 receptor blockade as immunotherapy. Infect. Immun. 70:6284-6293.
18. Murray, H. W., A. L. Moreira, C. M. Lu, J. L. DeVecchio, M. Matsuhashi, X. Ma, and F. P. Heinzel. 2003. Determinants of response to interleukin 10 receptor blockade immunotherapy in experimental visceral leishmaniasis. J. Infect. Dis. 188:458-464.
19. Murray, H. W., K. C. Flanders, D. D. Donaldson, J. P. Sypek, P. J. Gotwals, J. Liu, and X. Ma. 2005. Antagonizing deactivating cytokines to enhance host defense and chemotherapy in experimental visceral leishmaniasis. Infect. Immun. 73:3903-3911.
20. Murray, H. W., C. W. Tsai, J. Liu, and X. Ma. Submitted for publication.
21. Noben-Trauth, N., R. Lira, H. Nagase, W. E. Paul, and D. L. Sacks. 2003. The relative contribution of IL-4 receptor signaling and IL-10 to susceptibility to Leishmania major. J. Immunol. 170:5152-5158.
22. Satoskar, A., H. Bluethmann, and J. Alexander. 1995. Disruption of the murine interleukin-4 gene inhibits disease progression during Leishmania mexicana infection but does not increase control of Leishmania donovani infection. Infect. Immun. 63:4894-4899.
23. Satoskar, A. R., S. Rodig, S. R. Telford, A. A. Satoskar, S. K. Ghosh, F. von Lichtenberg, and J. R. David. 2000. IL-12 gene-deficient C57BL/6 mice are susceptible to Leishmania donovani but have diminished hepatic pathology. Eur. J. Immunol. 30:834-839.
24. Sosa, M. R., L. E. Rosas, A. N. J. McKenzie, and A. R. Satoskar. 2001. IL-13 gene-deficient mice are susceptible to cutaneous Leishmania mexicana infection. Eur. J. Immunol. 31:3255-3260.
25. Stager, S., J. Alexander, K. C. Carter, F. Brombacher, and P. M. Kaye. 2003. Both interleukin-4 (IL-4) and IL-4 receptor signaling contribute to the development of hepatic granulomas with optimal antileishmanial activity. Infect. Immun. 71:4804-4807.
26. Taylor, A., and H. W. Murray. 1997. Intracellular antimicrobial activity in the absence of interferon-: effect of interleukin 12 in experimental visceral leishmaniasis in interferon- gene-disrupted mice. J. Exp. Med. 185:1231-1239.
27. Wilson, M. E., S. M. B. Jeronimo, and R. D. Pearson. 2005. Immunopathogenesis of infection with the visceralizing Leishmania species. Microb. Pathog. 38:147-160.(Henry W. Murray, Christin)
ABSTRACT
Leishmania donovani-infected interleukin-13–/– BALB/c mice showed impaired initial gamma interferon secretion and incomplete granuloma assembly at parasitized liver foci. Nonetheless, control of early parasite replication, resolution of liver infection, and responsiveness to antileishmanial chemotherapy were intact. By itself, interleukin-13 does not appear to materially influence acquired resistance in this intracellular infection.
TEXT
In experimental visceral leishmaniasis, host defense against intracellular Leishmania donovani is T cell dependent and involves a range of T-cell- and macrophage-activating cytokines (15, 16, 25). In L. donovani infection in the liver, interleukin-12 (IL-12) and gamma interferon (IFN-) figure prominently in granuloma assembly, macrophage activation, and parasite killing, driving acquired resistance and eventual near resolution of infection (4, 12, 15, 16, 23, 26). In addition, the same inflammatory response supports the efficacy of conventional antileishmanial chemotherapy, pentavalent antimony (Sb) (15).
L. donovani infection also provokes expression of Th2-cell-type cytokines (IL-4, IL-10, and IL-13) and transforming growth factor (18), ordinarily considered counterbalancing, suppressive factors. These cytokines probably limit tissue injury but to various degrees also derail Th1-cell responses, deactivate macrophages, and promote infection (3, 9, 11, 17, 19, 27). In L. donovani-infected, susceptible, wild-type (WT) BALB/c mice, neutralization or receptor blockade has demonstrated a striking deactivating effect for IL-10, modest suppressive roles for transforming growth factor and IL-13, and no role for IL-4 (19). Nevertheless, studies with L. donovani-infected IL-4–/– BALB/c mice indicate a less well appreciated effect for IL-4 in supporting Th1-type responses and limiting initial liver parasite replication (1, 22, 25). In addition, susceptibility to L. donovani is further enhanced in IL-4 receptor -deficient (IL-4R–/–) BALB/c mice, in which higher liver parasite burdens correlated with deficient IFN- secretion and impaired granuloma maturation. Since IL-13 also signals via IL-4 receptor , a separate, similarly early-acting antileishmanial role was inferred for IL-13 (25).
To formally test the role of IL-13 alone, IL-13 gene-disrupted mice on a BALB/c background (5) were infected intravenously with 1.5 x 107 hamster spleen-derived L. donovani amastigotes (1 Sudan strain) (19). However, the course of infection in the liver, measured microscopically with tissue imprints and expressed as Leishman Donovan units (LDU) (19), proved nearly indistinguishable from the course of liver infection for WT BALB/c animals (Fig. 1). In particular, the level of infection was similar at week 4, the point at which liver parasite burdens in IL-4R–/– mice exceeded those in WT controls, before both groups resolved infection at week 8 (25).
Nevertheless, IL-13–/– mice showed defects in two linked expressions of Th1-cell-associated defense against L. donovani, IFN- secretion and granuloma assembly (15, 16). IFN- was measured in serum by enzyme-linked immunosorbent assay, and a value of 0 was arbitrarily assigned to results showing <31 pg/ml, the limit of detectability (19). IFN- was not detected in uninfected mice, and in two experiments, levels were lower at week 2 in IL-13–/– (15 ± 16 pg/ml) than in WT (56 ± 21 pg/ml) animals (mean ± standard error of the mean [SEM], n = 6 to 7 mice per group; P > 0.05). However, week 4 levels increased in IL-13–/– mice (140 ± 57 pg/ml), suggesting that reduction in IFN- secretion was transient. While measuring IFN- in serum is a useful marker of Th1-cell-type responses, the physiologic implication of activity in serum (versus in situ IFN- expression at the infected tissue focus) is unknown.
IL-13–/– mice also failed to generate the anticipated early cellular reaction at parasitized Kupffer cell foci at week 2 (Fig. 2B) (16). While granulomas formed by week 4, 85% were small and scored as developing (immature) (16), having attracted relatively few recruited mononuclear cells (Fig. 2D). Thus, at week 4, there was little evidence of transition to the mature-appearing, mononuclear-cell-rich structures (Fig. 2C) associated with control over L. donovani in WT mice (16, 25). Subsequent observations indicated no further progression towards granuloma maturation, as IL-13–/– mice showed involution of most granulomatous foci at week 8, with residual epithelioid changes similar to those in WT mice (Fig. 2E and F).
Since both IFN- and mononuclear cell recruitment regulate the leishmanicidal response to Sb chemotherapy within parasitized tissue (13, 14), we anticipated a deficient response to treatment for IL-13–/– mice. However, the efficacy of both optimal- and suboptimal-dose Sb (sodium stibogluconate [Pentostam]) (19) was preserved (Table 1). Suboptimal-dose Sb was used to test for more-subtle effects potentially induced by the absence of IL-13.
Together, our results suggest that IL-13 promotes initial IFN- production and show that IL-13 influences tissue granuloma assembly and maturation. However, these experiments have not addressed the mechanism(s) by which IL-13 regulates these two expressions of the antileishmanial Th1 response. Possibilities include that IL-13's effects, as reported for IL-4 (1, 24), support Th1-cell development (contributing to initial IFN- secretion) and shape subsequent responses, including granuloma maturation. Alternatively, although ordinarily considered a suppressive-type cytokine, IL-13 might also act to downregulate other deactivating mechanisms (e.g., IL-10 [7]) which limit initial IFN- secretion and restrain granuloma development.
Nevertheless, the absence of the two aforementioned effects in IL-13-deficient mice did not materially influence acquired resistance or eventual resolution of L. donovani infection in the liver. Similar results for IFN- and granulomatous responses have been demonstrated well for IL-4–/– and in a more pronounced fashion with IL-4R–/– BALB/c mice (25). However, and in contrast to our findings (Fig. 1), these same two effects correlated with increased initial susceptibility to L. donovani in both IL-4–/– and IL-4R–/– mice (25), possibly indicating a more primary role for IL-4 in supporting initial acquired resistance. Since IFN--induced macrophage activation and granuloma formation are clear-cut expressions of the Th1-cell-type response which controls liver infection in this model (16, 17, 19), our findings with IL-13–/– mice suggest an early-acting, compensatory, or IFN--independent mechanism. Such mechanisms may involve IL-12 and tumor necrosis factor (26) or IL-18 (20). Similarly, L. donovani-induced granuloma assembly can also proceed in an IFN--independent fashion (18, 26). Further, albeit under separate conditions (10), L. donovani infection can also be controlled in the absence of a granulomatous response.
These same IL-13–/– BALB/c mice as well as their C57BL/6 counterparts have also been tested with cutaneous L. major (5) and L. mexicana (2, 24) infection. These studies produced variable results for the role of IL-13, ranging from no role (24) to a protective (2) or a suppressive (2, 5) role. In IL-4R–/– mice, IL-13's inferred role in cutaneous infection has been similarly variable, depending upon the Leishmania strain tested (2, 8, 21). In our experiments, in which we used an L. donovani strain different from that tested with IL-4R–/– mice (25), the absence of IL-13 did not accelerate control of liver infection, enhance granuloma assembly, heighten IFN- secretion, or increase responsiveness to Sb chemotherapy-linked expressions of raised Th1-cell reactivity well expressed, for example, in IL-10–/– mice (17). Thus, IL-13 by itself does not appear to exert suppressive Th2-type cytokine effects in this model. Conversely, infection in IL-13–/– mice was not exacerbated, as would be anticipated (17, 19) if IL-13 played a meaningful prohost defense role. It is also worth pointing out that our observations are limited to the liver; thus, it is possible that different results might have been seen with the spleen, for example.
Nevertheless, endogenous IL-13 does have transient or limited effects in L. donovani infection but under quite different conditions: in conjunction with deficient IL-4 (e.g., in IL-4R–/– mice [26]), for intact WT mice injected with soluble IL-13 receptor 2 (IL-13R2) immunoglobulin G Fc (19), and for IL-13R2–/– mice (19). The effect of IL-13 again varies, however, depending upon the setting. BALB/c IL-4R–/– mice are initially more susceptible to L. donovani at week 4, suggesting an initially protective, albeit dispensable action for IL-13, since infection resolves normally by week 8 (26). Inhibition of IL-13 by IL-13R2 immunoglobulin G Fc treatment enhances inhibition of L. donovani replication in WT BALB/c mice but does not permit parasite killing (19). Finally, for IL-13R2–/– mice, which phenotypically resemble IL-13 transgenic animals (6), excess IL-13 suppresses IFN- secretion and granuloma assembly and promotes L. donovani infection; however, for IL-13R2–/– mice, the latter effect of IL-13 is also transient (19).
ACKNOWLEDGMENTS
This work was supported by NIH grants AI 16369 (H.W.M.) and AI 45899 (X.M.).
We are particularly grateful to A. Mackenzie for helping us acquire the IL-13–/– mice he developed.
REFERENCES
1. Alexander, J., K. C. Carter, N. Al-Fasi, A. Satoskar, and F. Brombacher. 2000. Endogenous IL-4 is necessary for effective drug therapy against visceral leishmaniasis. Eur. J. Immunol. 30:2935-2943.
2. Alexander, J., F. Brombacher, H. A. McGachy, A. N. McKenzie, W. Walker, and K. C. Carter. 2002. An essential role for IL-13 in maintaining a non-healing response following Leishmania mexicana infection. Eur. J. Immunol. 32:2923-2933.
3. deVries, J. E. 1998. The role of IL-13 and its receptor in allergy and inflammatory responses. J. Allergy Clin. Immunol. 102:165-169.
4. Engwerda, C. R., M. L. Murphy, S. E. Cotterell, S. C. Smelt, and P. M. Kaye. 1998. Neutralization of IL-12 demonstrates the existence of discrete organ-specific phases in the control of Leishmania donovani. Eur. J. Immunol. 28:669-680.
5. Matthews, D. J., C. L. Emson, G. J. McKenzie, H. E. Jolin, J. M. Blackwell, and A. N. J. McKenzie. 2000. IL-13 is a susceptibility factor for Leishmania major infection. J. Immunol. 164:1458-1462.
6. McKenzie, A. N. J., and P. G. Fallon. 2003. Decoy receptors in the regulation of T helper cell type 2 responses. J. Exp. Med. 197:675-679.
7. McKenzie, G. J., C. L. Emson, S. E. Bell, S. Anderson, P. Fallon, G. Zurawski, R. Murray, R. Grencis, and A. N. J. McKenzie. 1998. Impaired development of Th2 cells in IL-13-deficient mice. Immunity 9:423-432.
8. Mohrs, M., B. Ledermann, G. Khler, A. Dorfmüller, A. Gessner, and F. Brombacher. 1999. Differences between IL-4- and IL-4 receptor -deficient mice in chronic leishmaniasis reveal a protective role for IL-13 receptor signaling. J. Immunol. 162:7302-7308.
9. Murphy, M. L., U. Wille, E. N. Villegas, C. A. Hunter, and J. P. Farrell. 2001. IL-10 mediates susceptibility to Leishmania donovani infection. Eur. J. Immunol. 31:2848-2856.
10. Murray, H. W., K. E. Squires, C. D. Miralles, M. Y. Stoeckle, A. M. Granger, A. Granelli-Piperno, and C. Bogdan. 1992. Acquired resistance and granuloma formation in experimental visceral leishmaniasis: differential T cell and lymphokine roles in initial versus established immunity. J. Immunol. 148:1858-1865.
11. Murray, H. W., J. Hariprashad, and R. L. Coffman. 1997. Behavior of visceral Leishmania donovani in an experimentally-induced Th2 cell-associated response model. J. Exp. Med. 185:867-874.
12. Murray, H. W., C. Montelibano, R. Peterson, and J. P. Sypek. 2000. Interleukin 12 regulates the response to chemotherapy in experimental visceral leishmaniasis. J. Infect. Dis. 182:1497-1503.
13. Murray, H. W., and S. Delph-Etienne. 2000. Role of endogenous gamma interferon and macrophage microbicidal mechanisms in host response to chemotherapy in experimental visceral leishmaniasis. Infect. Immun. 68:288-293.
14. Murray, H. W. 2000. Mononuclear cell recruitment, granuloma assembly, and response to treatment in experimental visceral leishmaniasis: intracellular adhesion molecule 1-dependent and -independent regulation. Infect. Immun. 68:6294-6299.
15. Murray, H. W. 2001. Clinical and experimental advances in treatment in visceral leishmaniasis. Antimicrob. Agents Chemother. 45:2185-2197.
16. Murray, H. W. 2001. Tissue granuloma structure-function in experimental visceral leishmaniasis. Int. J. Exp. Pathol. 82:249-267.
17. Murray, H. W., C. M. Lu, S. Mauze, S. Freeman, A. L. Moreira, G. Kaplan, and R. L. Coffman. 2002. Interleukin-10 (IL-10) in experimental visceral leishmaniasis and IL-10 receptor blockade as immunotherapy. Infect. Immun. 70:6284-6293.
18. Murray, H. W., A. L. Moreira, C. M. Lu, J. L. DeVecchio, M. Matsuhashi, X. Ma, and F. P. Heinzel. 2003. Determinants of response to interleukin 10 receptor blockade immunotherapy in experimental visceral leishmaniasis. J. Infect. Dis. 188:458-464.
19. Murray, H. W., K. C. Flanders, D. D. Donaldson, J. P. Sypek, P. J. Gotwals, J. Liu, and X. Ma. 2005. Antagonizing deactivating cytokines to enhance host defense and chemotherapy in experimental visceral leishmaniasis. Infect. Immun. 73:3903-3911.
20. Murray, H. W., C. W. Tsai, J. Liu, and X. Ma. Submitted for publication.
21. Noben-Trauth, N., R. Lira, H. Nagase, W. E. Paul, and D. L. Sacks. 2003. The relative contribution of IL-4 receptor signaling and IL-10 to susceptibility to Leishmania major. J. Immunol. 170:5152-5158.
22. Satoskar, A., H. Bluethmann, and J. Alexander. 1995. Disruption of the murine interleukin-4 gene inhibits disease progression during Leishmania mexicana infection but does not increase control of Leishmania donovani infection. Infect. Immun. 63:4894-4899.
23. Satoskar, A. R., S. Rodig, S. R. Telford, A. A. Satoskar, S. K. Ghosh, F. von Lichtenberg, and J. R. David. 2000. IL-12 gene-deficient C57BL/6 mice are susceptible to Leishmania donovani but have diminished hepatic pathology. Eur. J. Immunol. 30:834-839.
24. Sosa, M. R., L. E. Rosas, A. N. J. McKenzie, and A. R. Satoskar. 2001. IL-13 gene-deficient mice are susceptible to cutaneous Leishmania mexicana infection. Eur. J. Immunol. 31:3255-3260.
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