Experimental cutaneous leishmaniasis. II. Effects of immunosuppression and antigenic competition on the course of infection with leishmania enriettii in the guinea-pig

Intradermal inoculation of the guinea-pig with Leishmania enriettii results in a self-healing cutaneous lesion which provides a laboratory model of human cutaneous leishmaniasis and which is dominated by cell-mediated immunological responses (Bryceson et al., 1970). In this study we sought to design experimental situations resembling non-healing forms of cutaneous leishmaniasis in man and to determine whether these experimental situations were accompanied by abnormalities in the immunological response to infection. This paper describes three procedures which impair the resistance of guinea-pigs to leishmanial infection: (i) induction of partial immunological tolerance to leishmanial antigen; (ii) systemic injection of anti-lymphocyte serum (ALS); and (iii) regional antigenic competition produced by multiple injections of bacterial adjuvants.

Injection of soluble leishmanial antigen (PSA) during the third week of foetal life suppressed resistance to neonatal infection with L. enriettii; local infections were severe and were accompanied by metastatic spread and by impaired development of delayed hypersensitivity (DH). Injection of PSA into the 6-week foetus and into the adult guinea-pig led to impaired DH after leishmanial infection, but resistance to infection was only slightly suppressed. Transient impairment of DH was induced by a short injection course of adult animals with ALS during the first 3 weeks of infection, which resulted in large primary lesions with temporary metastatic spread.

Multiple regional injections of tubercle- and corynebacterial-adjuvant emulsions markedly suppressed resistance to subsequent leishmanial infection; large ulcerative lesions were accompanied by widespread nodular metastases, the unusual appearance of haemagglutinating antibody, and death of some animals.

There was no impairment of DH to PSA; in fact, this was temporarily enhanced during the first 6 weeks of leishmanial infection of the tubercle-adjuvant group. This suppression of resistance could not be attributed to systemic desensitization of DH to bacterial antigen or to the local sclerosing effects of adjuvant emulsion; the term `regional antigenic competition' was therefore employed. Both the induction of partial tolerance and the injection of ALS selectively impaired paracortical responses in lymph nodes draining leishmanial infections; however, in regional antigenic competition the lymph nodes were infiltrated with macrophages but both follicular and paracortical responses were prominent.

Suppression of resistance to L. enriettii was not related simply to impairment of DH; for there was overall dissociation of protective, allergic and antibody responses in these suppressed animals. The relationship of cellular immune mechanisms to cutaneous leishmaniasis was viewed in two ways. First, it was inferred that resistance of guinea-pigs to L. enriettii requires both successful induction of cell-mediated immunity and functional integrity of the regional lymphoid system at the time of infection. Second, it was suggested that nonhealing forms of human cutaneous leishmaniasis may arise from defective coordination of surveillance, inflammatory and adjuvant functions of the cellular immune response to leishmanial antigens. It was concluded that interference with cellular immune responses in the guinea-pig led to experimental infections which resembled some features of more generalized cutaneous leishmaniasis in man.