The basic defect in lepromatous leprosy is the selective unresponsiveness of T cells to the antigens of Mycobacterium leprae (1). This defect may be partial or complete (2) and does not appear to change with prolonged chemotherapy (3). A lack of T cell-derived lymphokines such as IFN-y and IL-2 could account for the inability of macrophages and other cells to eliminate M. leprae .Attempts to circumvent T cell unresponsiveness have already been initiated in both in vitro systems (2, 4-6) and in the confines of the cutaneous lesions. Initial observations have been reported on the efficacy of crossreacting antigens such as purified protein derivative of tuberculin (PPD)' and the lymphokine rIFN-. y (7-10) . In the case of PPD, intradermal administration has led to a long-lived emigratory mononuclear leukocyte response, the local destruction of parasitized macrophages, and a striking reduction in the number of M. leprae within 21 d. These responses and the accompanying modification of cellular subsets are evidence of a vigorous cell-mediated immune reaction in the environment ofa lepromatous lesion . Similar observations have been made after IFN-y administration (manuscript in preparation).We have now extended these observations to the use of human rIL-2. This lymphokine serves as an autocrine T cell growth factor, and induces the formation of lymphokines with other functions (11,12). We report results on the use of small doses of IL-2, in the skin of lepromatous patients, and the reconstitution of cutaneous cellular immunity. Volume 169 March 1989 893-907 Materials and Methods Patient Population . 35 patients, 18-60 yr old, 23 with lepromatous leprosy (LL) and 12 with borderline lepromatous leprosy (BL) (13), were selected for the intradermal administra-

Leprosy is a chronic granulomatous disease of man caused by the intracellular bacterium Mycobacterium leprae (1) . The clinical manifestations of the disease range from single paucibacillary lesions (tuberculoid) to disseminated multibacillary involvement of almost the entire skin (lepromatous) . The polarity of the disease depends in large measure on the ability of the host to mount a cellular immune response to the infectious agent (reviewed in reference 2) . To study the mechanisms underlying these delayed-type cell-mediated reactions, we have selected the response to a purified protein derivative of tuberculin (PPD)' in skin of the naturally sensitized hosts . We have already commented on the stimulation of keratinocyte proliferation and the induction ofMHC class II antigen (3), the local production of macrophage-activating lymphokines, the induction and localization of y IP-10 (4), and the influence of the delayed-type hypersensitivity reaction on the distribution of T6+ Langerhans cells (5) . More recently we have reported that the cellular response to PPD leads to the clearance of M. leprae from the skin of lepromatous patients (6) .In these studies we now present a detailed temporal examination of an effective tuberculin reaction in the skin of patients with lepromatous leprosy and comment on the determinants associated with the disposal of M. leprae .Volume

The purpose of this study was to evaluate the effects of a delayed-type cell-mediated immune response to Mycobacterium tuberculosis antigen on the Mycobacterium leprae load in the skin of leprosy patients. Twelve patients with the lepromatous form of leprosy have been injected intradermally with 5 units of the purified protein derivative of tuberculin (PPD). Ten individuals responded with areas of induration ranging from 12 to 21 mm in diameter, and two were unresponsive (<10 mm). Twenty-one days thereafter, the injected and control sites were blopsied, and the histology, number of acid-fast bacilli, nature and phenotype of the emigrant cells, and ultrastructural characteristics of the lesions were evaluated. Eight of the 10 responding patients showed reductions in the number of acid-fast bacilli by factors ranging from 5 to 10,000. Two responders and both nonresponders exhibited no discernible decline in the number of organisms. The reduction in bacillary load was correlated with an intense mononuclear cell infiltrate, the maintenance of a high CD4' T-cell/CD8' T-cell ratio, the formation of granulomata, and the extensive destruction of previously parasitized macrophages.Lepromatous leprosy is characterized by a selective inability of T cells to respond to Mycobacterium leprae antigens and to generate a cell-mediated immune response (reviewed in ref. 1). In association with this defect, helper T cells fail to migrate and to accumulate in the dermal lesions, and adequate amounts of lymphokines are not synthesized and released locally (2, 3). This absence of local lymphokines leads to a failure of macrophage activation, and these cells serve as permissive hosts for the bacilli (4). M. leprae then multiply within the secondary lysosomes of the vacuolar apparatus to levels as high as 109 organisms per g of skin (reviewed in ref. 5).Patients with lepromatous leprosy do react, however, to other mycobacterial antigens, including those contained in the purified protein derivative of tuberculin (PPD) with a delayed-type cell-mediated response (6). We suspected that the generation of a tuberculin reaction in the dermal leprosy lesions might supply the deficient cell subsets and cytokines and have a beneficial effect on the clearance of organisms.Our initial observations on the response to PPD in the skin of lepromatous leprosy patients have been reported. These include the emigration of large numbers of helper T cells into the dermis (7), the local production of the macrophageactivating lymphokine 'y interferon and its induced product IP-10 (8), the induction of HLA class II (Ia) antigens on the cells of the dermis and epidermis (7), and the accumulation of dermal Langerhans cells (9)-an important accessory cell for T-cell responses (10). We now have extended these studies and have evaluated the effectiveness of this second-party, cell-mediated reaction to influence the disposal of M. leprae. Our results indicate a striking reduction in the local bacillary load, which may be by a factor as large as 10,000. MATERI...