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Although opioid peptides such as methionine (met)-enkephalin have been previously shown to enhance or suppress immune responses, few studies in animal models have addressed the immunomodulatory activity of their metabolic derivatives. Hairless (IAF/HA-HO) guinea pigs immunized with Freund's complete adjuvant containing Mycobacterium tuberculosis and repeatedly skin tested with purified protein derivative of tuberculin (PPD) display high levels of stable delayed-type hypersensitivity (DTH) to PPD. Met-enkephalin (YGGFM) and two of its metabolites (YGG, YG) enhanced and accelerated PPD-elicited DTH inflammatory reactions when injected together with elicitor in these animals. At 24 h, 5 x 10(-3) pmol met-enkephalin significantly enhanced DTH responses by 30% over PPD alone, while 5 x 10(-5) pmol of YGG and 5 x 10(-9) pmol of YG significantly enhanced these responses by 62 and 32%, respectively. At much higher doses (5 x 10(3) pmol), met-enkephalin and its metabolites significantly suppressed DTH reactions by 25-32%. Tyrosine and glycine had no effect on PPD-elicited DTH. All DTH reactions (control, enhanced, suppressed) displayed typical perivascular mononuclear cell infiltrates. We conclude that the immunoactivity of met-enkephalin resides in its first two amino acids and suggest that cleavage of enkephalin molecules to YG occurs in serum and/or on the cell surface., (Copyright 2004 S. Karger AG, Basel)

IL-1alpha and IL-1beta are potent inflammatory cytokines that contribute to a number of normal physiologic processes and to the development of a number of inflammatory diseases. Two IL-1R, the type I and type II receptors, have been identified. This work describes the derivation and characterization of mice deficient in expression of the type I IL-1R (IL-1RI). IL-1RI-deficient mice were viable and fertile, but failed to respond to IL-1 in a variety of assays, including IL-1-induced IL-6 and E-selectin expression and IL-1-induced fever. Similar to IL-1beta-deficient mice, IL-1RI-deficient mice had a reduced acute phase response to turpentine. In contrast, IL-1RI-deficient mice had a reduced delayed-type hypersensitivity response and were highly susceptible to infection by Listeria monocytogenes. These data demonstrate that the IL-1RI is essential for all IL-1-mediated signaling events examined, and that both IL-1alpha and IL-1beta are critical to the animals' response to injury and infection. These data also demonstrate that IL-1 function is not required for normal development or homeostasis.

Methionine-enkephalin (Met-Enk) and leucine-enkephalin (Leu-Enk) belong to family of opioid peptides. In vivo studies on immunomodulating activity of enkephalins performed in the rat revealed the following: (a) both neuropentapeptides showed a dual, dose-dependent effect, i.e., high doses suppressed while low doses potentiated immune responses; (b) Met-Enk is more potent immunomodulator than Leu-Enk; (c) high doses of Met-Enk suppressed immune inflammatory reactions, such as systemic anaphylactic shock, Arthus and delayed hypersensitivity skin reactions to protein antigen, allograft rejection, adjuvant arthritis, and experimental allergic encephalomyelitis. Met-Enk is more efficient when applied intracerebroventricularly. A preliminary clinical trial showed that intrathecally given Met-Enk exerted a beneficial effect on 13 patients with chronic severe progressive multiple sclerosis.

Maximal complexing of alpha 2-macroglobulin (alpha 2M) and kallikrein (KK) occurs at a temperature of 22-24 rather than at 37 degrees C. The protease expressivity of the complex is also maximal at 22-24 degrees C. alpha 2M-KK complex, sustained permeability changes in guinea pig skin. These findings suggest that the complex, rather than free KK, could play a role in the kinin release reported in some late-phase reactions, some instances of delayed-type hypersensitivity and some cold-induced reactions.

Evidence is presented to indicate that there exists in lymphoid tissue, as a result of transforming lymphocytes, a new lymphokine which is chemotactically specific for lymphocytes, called 'lymphotactin'. Lymphotactin has been purified to electrophoretic homogeneity; has a molecular weight of 10,500 D and an isoelectric point of 5.9. Its role in amplifying the immune defense system by recruitment of naive lymphocytes into propinquity with the challenging antigens is suggested. Purification of macrophage migration inhibitory factor from thymus extracts to electrophoretic homogeneity leads to a compound of molecular weight of 36,500 D and an IEP of 6.9. Chemically it contains sialic acid and o-methyl glucopyranoside as its only carbohydrates. Purified MIF activates the macrophage phagocytically. Skin reactive factor and lymph node permeability factor have been isolated and purified and are found to be inhibited by pepstatin and antihistamine and to have an isoelectric point of pH 4.2 and a molecular weight of 50,000--100,000 D. It is believed that this anionic permeability increasing agent actually arises from the lysosomes of macrophages and lymphoblasts (the normal small lymphocyte having essentially no lysosomal organelles). The mononuclear cell infiltration characteristic of crude SRF and LNPF may proceed from their being contaminated with lymphotactin.

The neuropeptide substance P modulates the activities of a number of different leukocytes that characterize both acute and delayed inflammatory responses. Substance P may play a role in the pathogenesis of such diverse diseases as arthritis, asthma, and inflammatory bowel disease.

We examined the interrelationships between leukocyte adherence (ADH), polymorphonuclear neutrophil (PMN) chemotaxis (CTX), and PMN delivery to an inflammatory focus in hospitalized patients. Patients included 25 men and 17 women, with a mean age of 62.8 years, who were admitted for major elective surgery. The patients were studied preoperatively and on the second and seventh postoperative days. Leukocyte adherence increased on the second postoperative day (82.3%, P less than .05) and remained elevated on the seventh postoperative day (81.6%). Polymorphonuclear neutrophil chemotaxis decreased significantly on the second postoperative day (3.4 to 2.9 cm, P less than .05), but returned to normal by the seventh postoperative day. The PMN delivery to skin-window chambers decreased markedly on the second postoperative day (1.28 million cells, P less than .05) with a further decrease on the seventh postoperative day (0.82 million cells). There was no correlation between in vitro PMN CTX and in vivo cell delivery. We conclude that major surgery leads to increased ADH, decreased PMN CTX, and diminished PMN delivery to areas of inflammation. However, a single measure of PMN function such as in vitro PMN CTX does not, alone, reflect in vivo PMN delivery to areas of inflammation.