Phase II study of recombinant alpha-2 interferon in resistant multiple myeloma.

A multicenter phase II study of INTRON, recombinant alpha-2 interferon (Schering Corp, Kenilworth, NJ), in patients with relapsing or refractory myeloma was initiated. Patients received either intravenous therapy for two weeks followed by subcutaneous therapy or subcutaneous dosing from initiation of treatment. Of 38 evaluable patients, 19 were refractory and 19 had relapsed at entry. Twenty-five of 38 had received prior treatment with multiple drugs. Responses were seen among 2/19 refractory patients and 5/19 relapsing patients. Three of seven responders continue to respond for more than one year while receiving maintenance therapy. Most patients experienced improvement in bone pain, and one patient, with a complete response, had healing of bone lesions. Survival curves show a statistically significant improvement in survival for responders v nonresponders. INTRON was well-tolerated with only four patients discontinuing treatment due to adverse effects. Thirty-two percent of patients had hematologic toxicity requiring dose adjustment; however, there was no evidence of cumulative hematologic toxicity. No patients developed serum neutralizing factors to interferon. Additional trials are warranted to study the activity of INTRON in previously untreated patients.

Effects of muramyl dipeptide treatment on resistance to infection with Toxoplasma gondii in mice.

Studies were carried out to determine whether treatment of mice with the synthetic adjuvant muramyl dipeptide afforded any resistance to infection with the obligate intracellular protozoan Toxoplasma gondii. Marked resistance to lethal challenge infection was observed in CBA but not C57BL/6 mice pretreated with muramyl dipeptide. In CBA mice, a single muramyl dipeptide treatment administered 14, 7, or 4 days before Toxoplasma challenge did not afford protection, whereas mice treated at -1 day were highly resistant. Additional studies carried out to investigate the mechanisms underlying the enhanced resistance to Toxoplasma in muramyl dipeptide-treated mice failed to reveal either enhanced cytolytic antibodies to the parasite or evidence that peritoneal macrophages from treated mice were activated as determined in vitro by their microbicidal capacity for Toxoplasma or cytotoxic capacity for tumor target cells.

Induction of constant sensitivity to dinitrochlorobenzene in the cynomolgus monkey.

A technique for the induction of contact sensitivity in the cynomolgus monkey is described. Seventy percent of the monkeys gave a positive reaction when skin-tested 18 days after sensitization with dinitrochlorobenzene. When re-tested on day 27, both the number of reactors and the intensity of the reactions had increased. Histological examinations showed perivascular leukocytic infiltration with an increased proportion of mononuclear cells, typical of a delayed hypersensitive reaction.

Effects of treatment with muramyl dipeptide and certain of its analogs on resistance to Listeria monocytogenes in mice.

Studies were carried out to determine whether treatment of mice with the synthetic adjuvant muramyl dipeptide (MDP) afforded any resistance to infection with Listeria monocytogenes. Regardless of the timing, dose, or route of administration, there was no evidence that treatment with either MDP or two of its analogs (des-MDP or MDP-D-D) induced any resistance to listeria infection in BALB/c, CBA/J, or C57BL/6J mice. In contrast, pretreatment with MDP induced marked protection to infection with Streptococcus pneumoniae (type III).

Inhibition of rat intestinal anaphylaxis by various anti-inflammatory agents.

Adverse reactions to food may, in some cases, be due to IgE-mediated immune reactions to the ingested antigens. A mast cell protector has been shown to protect patients against challenge with food to which they are sensitive. An IgE-mediated intestinal anaphylaxis reaction in the rat has been developed as a model of some aspects of human food allergy. Using this model, a number of xanthones and other anti-inflammatory agents were tested for activity in inhibiting intestinal anaphylaxis. The compounds were also tested for inhibitory activity against the IgE-mediated rat passive cutaneous anaphylaxis reactions. The xanthones protected against both reactions, as did isoproterenol and cyproheptadine, while aspirin, indomethacin, and dexamethasone inhibited the intestinal but not the cutaneous reaction. This suggests that while IgE-triggered mediator release from mast cells is important in both reactions, other mechanisms may also be operative in the intestinal reaction. Furthermore, the use of xanthones and other anti-inflammatory compounds may be a useful mode of therapy in human food allergy.

Enhancement of host resistance against Trypanosoma cruzi infection by the immunoregulatory agent muramyl dipeptide.

N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide [MDP]) enhanced resistance against Trypanosoma cruzi infection in mice. This effect was evidenced by significant reductions in both parasitemias and mortality rates and increased survival time in MDP-treated animals compared with untreated infected mice. MDP effectively augmented host resistance when administered in any one of the following ways: (i) continuous subcutaneous release from an osmotic minipump for a 7-day period starting 2 days before infection; (ii) as a single dose of 0.5 mg injected intraperitoneally 48 h before infection; or (iii) injected intraperitoneally at 48-h intervals during the first 16 days after infection. CBA/J mice, which exhibit very low, insignificant augmentation of reticuloendothelial activity by MDP but are susceptible to its adjuvant effect, failed to manifest enhancement of resistance to T. cruzi infection when treated with MDP under regimens that cause increased resistance in other mouse strains. These results suggest that MDP enhances resistance against T. cruzi infection by stimulating the activity of the phagocytic cells of the host. Adjuvant effect appears to play either a less significant role or no relevant role, except when MDP is administered repeatedly after infection.

Synthesis and antiallergic activity of some mono- and disubstituted xanthone-2-carboxylic acids.

A series of xanthone-2-carboxylic acids, substituted mainly with electron-withdrawing groups, has been synthesized and assayed for antiallergic activity, using the passive cutaneous anaphylaxis (PCA) reaction in the rat. The effect of substituent type and substitution pattern on PCA neutralizing capacity is presented.

Intestinal anaphylaxis in the rat as a model of food allergy.

An animal model of food allergy has been developed in which some aspects of the allergic response could be quantified and the effects of various drugs evaluated. The change in permeability of the intestinal tract of actively sensitized rats, after oral challenge with the sensitizing antigen, was the parameter measured. Rats were sensitized by injection of egg albumin and B. pertussis vaccine to induce reaginic antibody to egg albumin. Two weeks after sensitization, 125I-labelled bovine serum albumin (125I-labelled BSA) was injected intravenously, followed by oral challenge with egg albumin. Pieces of intestinal tissue were obtained and the amount of 125I-labelled BSA determined in a gamma counter. The amount of 125I-labelled BSA in the intestinal tissue of sensitized and challenged rats regularly showed an increase of greater than 100% above values for control rats.

A selective inhibitor of the elicitation of immune-mediated reactions.

6-Chloro-17 alpha-hydroxypregna-1,4,6-triene-3,20-dione (CHP), a steroid having a progestin-type structure yet not having progestational activity, was found to exhibit moderate anti-inflammatory activity in a number of conventional tests for corticoid potency (e.g., thymolytic, granuloma, carrageenin edema). CHP was essentially equipotent, however, with cortisol in models of inflammation mediated via delayed hypersensitivity such as experimental allergic encephalomyelitis, adjuvant-induced arthritis, mouse skin graft, and mouse skin delayed hypersensitivity. In contrast to cortisol, which inhibits both 19-s and 7-s antibody formation, CHP does not diminish the number of cells producing either antibody.

Polysaccharide in delayed hypersensitivity. I. Pneumococcal polysaccharide as inducer and elicitor of delayed reactivity in guinea pigs.

A highly purified pneumococcal polysaccharide (Type II SSS) is a very efficient inducer of delayed hypersensitivity in random-bred guinea pigs. The cellular reactivity induced by this polysaccharide administered subcutaneously in complete Freund's adjuvant is of "tuberculin type"; it increases in intensity with time after the sensitizing injection, as judged by skin tests, the macrophage inhibition reaction and transfer of reactivity by peritoneal exudate cells. By contrast, the cellular reactivity induced by this immunogen in the absence of mycobacterial adjuvant has the characteristics of "Jones-Mote" reactivity. It is best seen at about 1 wk after sensitization; the reactions are characteristically little indurated and show histologic differences from tuberculin type responses; and the reactive state begins to disappear by 2-3 wk, with the accession of Arthus reactivity. This type of delayed reactivity may be related to an early phase of antibody synthesis.