DISRUPTION OF THE MURINE INTERLEUKIN-4 GENE INHIBITS DISEASE PROGRESSION DURING LEISHMANIA-MEXICANA INFECTION BUT DOES NOT INCREASE CONTROLOF LEISHMANIA-DONOVANI INFECTION

The growths of both cutaneous leishmaniasis and visceral leishmaniasis caused by Leishmania mexicana and Leishmania donovani, respectively, were measured in interleukin-4 (IL-4) knockout mice (IL-4-/-) and comp ared with those of similarly infected wild-type (IL-4+/+) control mice , While large, nonhealing, cutaneous lesions containing large numbers of parasites developed in IL-4+/+ mice subcutaneously infected with 5 x 10(6) L. mexicana amastigotes in the shaven rump, in IL-4-/- mice no lesions whatsoever developed and parasites were difficult to detect, Systemic spread and metastasis were also noted in IL-4+/+ but not IL-4 -/- mice, In contrast, IL-4-/- mice infected intravenously with 10(7) L. danovani amastigotes were found to have consistently higher parasit e burdens in their livers throughout infection than did their wild-typ e counterparts, However, these differences were only significant at 15 days postinfection, While the results reported here pertaining to L. donovani largely support previous studies, those related to L. mexican a provide new observations, The immunological responses of IL-4-/- and IL-4+/+ mice infected with L. mexicana were, therefore, examined both in vivo and in vitro, Although neither IL-4-/- nor IL-4+/+ mice infec ted with L. mexicana produced parasite-specific immunoglobulin G2a ant ibodies, IL-4+/+ mice, unlike IL-4-/- mice, developed significant immu noglobulin G1 antibody titers as infection progressed, indicating a Th 2-influenced response in wild-type mice, In addition, IL-4-/- mice, un like IL-4+/+ mice, developed a significant delayed-type hypersensitivi ty response, indicating a Th1-influenced response in IL-4-/- mice, Fol lowing in vitro stimulation, splenocytes from IL-4+/+ mice infected wi th L. mexicana displayed significantly higher antigen-specific prolife rative responses than did IL-4-/- mice. However, gamma interferon prod uction as measured from the supernatants of the in vitro splenocyte cu ltures of IL-4-/- mice was significantly higher than that from IL-4+/ mice, This again would indicate a predominantly Th1-influenced respon se in the absence of a Th2 response in IL-4-/- mice infected with L. m exicana. On the other hand, at the same time point, draining lymph nod e cells from IL-4+/+ mice produced significantly higher quantities of IC-5 than did those from IL-4-/- mice following in vitro antigenic sti mulation, These results demonstrate that, whereas IL-4 and/or Th2 lymp hocyte expansion is necessary for disease progression and the inhibiti on of a protective response in cutaneous infection caused by L. mexica na, such a role for Th2 cells in visceral leishmaniasis caused by L. d onovani cannot he demonstrated.