Paradoxical Augmentation of Tuberculin-Like Hypersensitivity, but Not Jones-Mote or Contact Hypersensitivity, in Cyclosporin A Treated Guinea Pigs

Abstract

Administration of cyclosporin A (CsA; 25 mg/kg) orally to guinea pigs from the time of immunization with ovalbumin (OVA) in complete Freund’s adjuvant, followed by drug withdrawal 4 days later, resulted in marked potentiation of classical, tuberculin-like delayed-hypersensitivity skin responses to OVA. However, no such augmentation of delayed-type hypersensitivity (DTH) to purified protein derivative (PPD) was demonstrated. The enhancing effect of CsA was also dependent on the dose of OVA used for both immunization and skin testing and on the interval between drug withdrawal and the elicitation of DTH. A single intraperitoneal injection of CsA (200 mg/kg) given 2 days before immunization also had an augmentary effect on 14-day responses to OVA. Similar treatment protocols, however, did not enhance Jones-Mote (cutaneous basophil) hypersensitivity to OVA or contact sensitivity reactions to dinitrofluorobenzene. Longer courses of CsA (25 mg/kg per os) between sensitization and skin testing severely depressed all three categories of type IV hypersensitivity reactions. Our observations may have important cautionary implications for the prospective management of immunologically mediated diseases of intermittent activity, including certain autoimmune disorders, where short courses of CsA might be contemplated.

Factors Influencing the Enhancement of Delayed-Type Hypersensitivity to Ovalbumin by Cyclosporin A in the Guinea Pig: Possible Role of Suppressor Cells

“…In keeping with previous observations [1,15], we found that 5-and 14-day courses of oral CsA given from the time of immunization significantly aug mented 14-and 28-day DTH reactions, respectively. The capacity of guinea pigs treated with CsA (day 0-4) to express augmented cellular immunity devel ops between days 8 and 14 [1], As we have shown in the present study, this ability can be adoptively trans ferred to naive recipients using lymphoid cells ob tained 10 days after immunization.…”

“…The present and previously reported data [1] clearly show that high-dose CsA given systemically before immunization with OVA can result in striking potentiation of antigen-specific DTH skin reactions. A similar, augmentory effect on cell-mediated immu nity has been reported for other anti-lymphocytic drugs, such as cyclophosphamide and methotrexate [8,11] and attributed to elimination of the rapid turn over precursors of suppressor cells.…”

“…The capacity of guinea pigs treated with CsA (day 0-4) to express augmented cellular immunity devel ops between days 8 and 14 [1], As we have shown in the present study, this ability can be adoptively trans ferred to naive recipients using lymphoid cells ob tained 10 days after immunization.…”

“…These include high-dosage CsA prior to immunization and short courses of the drug following immunization in the guinea pig [1,12,15], There is also evidence that in the mouse, CsA can break suppression of DTH induced by immunization with tolerogenic doses of sheep erythrocytes [2], The mechanism(s) underlying CsA-induced enhancement of cell-mediated immunity is at present obscure, but is of importance with regard to the use of CsA, both as an immunological tool and as a therapeutic agent in the management of various immunologically medi ated disorders where differing CsA treatment strate gies may be employed.…”

Cyclosporin A increases the pulmonary eosinophilia induced by inhaledAspergillusantigen in mice

“…This latter fmding contrasts with the results of Nogami et ai, who found that CsA efficiently blocked Ascaris antigen-induced pulmonary eosinophilia [35]. However, other reports showed that CsA caused an augmentation of DTH in rats or guinea pigs [36]. enhanced collagen-induced arthritis in rats [37].…”