An analysis of in vitro T cell responsiveness in lepromatous leprosy.

Abstract

Antimicrobial defense mechanisms are enhanced by antigen-specific T cell differentiation followed by activation of mononuclear phagocytes (1, 2). 3" Interferon (IFN-3,) ~ is an important mediator of both antimicrobial activity and hydrogen peroxide secretion in mononuclear phagocytes (3). A number of observations suggest that an immunological defect exists in lepromatous leprosy w_hich-allows the extensive replication of M. leprae within dermal macrophages (4). The skin lesions are relatively deprived of helper T cells (OKT4), which are an important source of IFN-3" (5-7). The exposure of peripheral blood T cells to M. leprae fails to result in appreciable T cell proliferation and synthesis of lymphokine, including IFN-3" (8-10). In contrast, the lymphocytes of patients with lepromatous leprosy can respond to l~ctins and other antigens to which they are sensitized (4,(8)(9)(10)(11)(12)(13). This had lead to the concept of selective anergy in which, either due to the absence ofM. leprae-reactive T cells and/or the activity of suppressor cells or factors, macrophage activation does not occur and microbial dissemination ensues (1 1-23).In the course of studies on the reversal of T cell nonresponsiveness with purified IL-2 in lepromatous leprosy patients (8), we were struck by the heterogeneous response to this T cell growth factor. We have therefore reexamined the responsiveness of T cells to M. leprae and other antigens, and evaluated their stimulation by recombinant IL-2 and their possible inhibition by suppressor cell populations. Materials and MethodsPatients. Patients (see Table I Abbreviations used in this paper: BCG, bacillus Calmette Guerin; C*, rabbit complement; Con A, concanavalin A; IFN-3,, immune (gamma) interferon; IL-2, interleukin 2; mAb, monoclonal antibodies.J. ExP. MED.

Immunologic tolerance in lymphatic filariasis. Diminished parasite-specific T and B lymphocyte precursor frequency in the microfilaremic state.

“…This, in turn, leads to a high intravascular antigen load that either "saturates" or fails to engage the appropriate subsets of antigen-presenting cells that would be responsible to deliver the appropriate costimulatory signal (35). Although states of immune unresponsiveness have been described in other helminth infections (e.g., schistosomiasis [36], onchocerciasis [37]), several protozoal infections (e.g., visceral leishmaniasis [38], malaria [39]), and the lepromatous form of the mycobacterial disease leprosy (40), only one study has attempted a quantification of antigen-specific T cells among the unresponsive individuals (41). In that study of eight patients with leprosy (four tuberculoid, four lepromatous), the frequencies of T cells responsive to mycobacterial antigens were significantly lower in lepromatous patients (1/13, 679-1/73,422) than in individuals with tuberculoid disease (1/3,656-1/10,906).…”

“…First, the limiting dilution studies in leprosy patients used unfractionated PBMC, allowing the possibility that monocytes may be actively suppressing the proliferation among T cells from lepromatous patients. Second, unlike bancroftian filariasis, the immunosuppression in lepromatous leprosy is generalized (40) and may result from nonspecific immunosuppression by mycobacterial antigens (42).…”

Expression and cytokine secretion in the states of immune reactivation in leprosy

“…Additional data from many laboratories have made important and also controversial contributions: i) addition of IL-2 to patient cultures restored the M. leprae unresponsiveness in some lepromatous patients (9); ii) addition of IL-4 to the cultures increased the pre-existing M. leprae response; iii) preincubation of patient cultures without any stimulus reversed the specific T cell unresponsiveness of lepromatous patients (10); iv) unresponsiveness to M. leprae could also be overcome in vitro by stimulation with M. leprae components in some patients.…”

The role of indoleamine 2, 3-dioxygenase in lepromatous leprosy immunosuppression

“…While investigated extensively both in vivo and in vitro, the fact that lepromatous (LL) patients do not present a T cell response to Mycobacterium leprae remains undecipherable [1,2]. In these patients, disseminated skin lesions with high bacterial loads and negative lepromin skin tests are associated with the absence of both T cell proliferation and interferon (IFN)-g production in vitro by M. leprae-stimulated blood cells [3,4].…”