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The production of macrophage migration inhibitory factor (MIF) and immune interferon (IF) by concanavalin A (Con A)-stimulated cultures of thymus, lymph node and spleen cells was investigated. It was found that all cultures produced MIF activity, whereas only spleen cells produced marked IF activity. The capacity to produce IF was found to be correlated with the macrophage content of a cell preparation as evidenced by staining for esterase-positive cells. Furthermore, column-purified spleen T cells produced MIF but no IF. Migration inhibition caused by residual mitogen could be ruled out. On the other hand, when macrophages grown from bone marrow cells were pre-exposed to supernatants of mitogen-stimulated lymphocytes, IF activity was released into freshly added medium while no significant MIF activity was found. IF was also found in supernatants of macrophage cultures after exposure to conventional inducers in vitro (polyinosinic-polycytidylic acid, Corynebacterium parvum) or in vivo (C. parvum), whereas no MIF was detected. An anti-Type I IF serum neutralized IF in supernatants from Con A-stimulated spleen cells but did not affect MIF in the same supernatants. This indicates that IF and MIF activity are associated with different molecules. It is, therefore, concluded that under the described conditions, IF and MIF are produced by different cells. T cells are the prime producers of MIF while IF is released by macrophages following induction by lymphokines.
Guinea-pig macrophage migration inhibitory factor (MIF), obtained by the stimulation of sensitized lymph node cells with tuberculin PPD, was characterized as a glycoprotein by the following criteria: (a) its activity is destroyed by 0.02 M sodium periodate; (b) when MIF-containing culture fluids are subjected to precipitation by perchloric acid (final concentration 1 M), the inhibitory activity is recovered in the supernatant; and (c) MIF binds to Sepharose-linked concanavalin A and can be eluted with methyl-alpha-D-glucopyranoside. When MIF-containing culture supernatants are fractionated by isoelectrofocussing, migration inhibitory activity is recovered in a fraction with an isoelectric point of 4.4--4.6.
Spleen cells of C57B1/6J mice immunized with complete Freund's adjuvant produced macrophage migration inhibitory factor (MIF) when incubated in vitro with tuberculin purified protein derivative (PPD). For optimal MIF production spleen cells were cultured for 48 h in a serum-free medium, at a concentration of 2 x 10(7) cells/ml. MIF was assayed in a xenogenic system, using oil-induced guinea pig peritoneal exudate cells as targets. MIF synthesis could also be induced by pulsing spleen cells for 2 h with concanavalin A, phytohemagglutinin, pokeweed mitogen or lipopolysaccharide, followed by culture in plain medium. No MIF secretion was induced by incubation of spleen cells with anti-theta or rabbit anti-mouse IgG sera. Cells producing MIF in response to PPD were characterized as B cells by virtue of being insensitive to anti-theta serum and complement, by being retained on nylon wool, glass bead and anti-Ig colums and by the presence of Fc receptors. PPD-stimulated T cells did not produce MIF. PPD-induced mouse spleen cell MIF demonstrated a moderate loss of activity by heating at 56 and 80 degrees C and was completely inactivated after digestion with chymotrypsin. By fractionation on Sephadex G-200, migration inhibitory activity was recovered in a molecular range of 100,000-12,400 daltons.
The influence of the thymus on the production of the macrophage migration inhibitory factor (MIF) was studied in C57BL and CBA mice thymectomized at 4--6 weeks of age. On the 1--21st day after the operation they were immunized intraperitoneally with complete Freund's adjuvant. MIF production stimulated by tuberculin was determined on the maximum of the immune response. MIF production was abolished in mice of both lines already during the first days. To elucidate a relationship between MIF production and the presence of the thymus the former was investigated in the thymectomized "nude" mice. The mice showed no MIF production. It was found as well that thymectomy can interrupt the immune response in early stages of its development and completely eliminates MIF production the first days after immunization. Moreover, thymectomy in adult mice also changes spontaneous migration of macrophages both in immunized and non-immunized mice. These changes were more pronounced in C57BL mice.
Treatment of guinea-pig macrophage migration inhibitory factor (MIF) containing culture supernatants with the denaturing agents guanidine hydrochloride (Gu HCl) or urea, in the presence or absence of the reducing agent 2-mercaptoethanol (2-ME), or with sodium dodecyl sulphate (SDS), does not destroy biological activity. Alkylation of reduced MIF preparations results in a considerable decrease or total loss of MIF activity. Treatment of supernatants with the combinations, Gu HCl and 2-ME or urea and 2-ME results in the recovery of MIF activity in association with molecules less than 30,000 in molecular weight (mol. wt). After removal of the agents by dialysis, MIF activity is found associated with molecules larger than 30,000. The reduction in mol. wt is dependent on the presence of 2-ME. When MIF-containing supernatants are treated with urea and SDS and fractionated by preparative polyacrylamide gel electrophoresis (PAGE) in the presence of the same agents, MIF activity is recovered in the mol. wt range of 42,000--80,000. When supernatants are treated with 2-me, in addition to urea and SDS, and preparative PAGE is performed in their presence, MIF activity is found associated with material having a mol. wt of 15,000--18,000. Analytical SDS-PAGE of this fraction reveals two or three closely grouped bands corresponding to the above mol. wt range.
Sixty three cancer cases who received minimum of the removal of the main tumor constitute the subjects of the present study. Macrophage migration inhibitory factor (MIF) of peripheral blood lymphocytes was studied using extirpated autochthonous tumor tissues as antigen and guinea-pig peritoneal exudative cells as indicator cells immediately before the operation and the fourth postoperative week. The results indicated that in those cases of relatively early stage, i.e. Stages I and II, whose tumor was believed to have been removed completely, MIF turned negative in 7/9 (77.8 per cent) after the operation, while in others with advanced cancer of Stage IV in which the tumor bearing tissue was probably not completely removed, MIF turned positive in most cases (13/17: 75.6 per cent) postoperatively, even though it was negative before the operation. In the cases of Stage III with cancer progressed to an intermediate degree, in about half of the cases (7/11: 63.6 per cent) MIF turned negative after the operation and in the other half (7/10: 70 per cent) MIF became positive postoperatively, suggesting that for MIF to persist the presence of certain amount of tumor tissue is necessary.
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The pericardial effusion in a case of rheumatoid pericarditis was studied to determine whether immune complexes and mediators of cellular immunity, represented by migration inhibitory factor (MIF), were present. MIF-like activity was detected in the pericardial fluid, but only traces of immune complexes were revealed by ultracentrifugation. The MIF-like activity was partially characterized by column fractionation and sugar inhibition tests. The role of lymphokines in the pathogenesis of this case of rheumatoid pericarditis is strongly suggested.
The responsiveness to macrophage migration inhibitory factor (MIF) of peritoneal exudate cells (PEC) from the LPS unresponsive C3H/HeJ and C57BL/10ScCR mice was assessed by the indirect agarose microdroplet macrophage migration inhibition assay. No migration inhibition with PEC from C3H/HeJ nor C57BL/10ScCR mice was detected, whereas PEC from both C3H/HeN and C57BL/10Sn mice were significantly inhibited by even a 1/32 dilution of MIF-containing supernatants. Responsiveness to MIF of C3H/HeJ PEC could, however, be induced. In vivo inoculations of Mycobacterium bovis, strain BCG, 7 days before in vitro assay rendered C3H/HeJ PEC responsive to MIF. The lack of responsiveness to MIF by C3H/HeJ PEC appeared related to some form of suppression, since a mixture of PEC from C3H/HeN mice with 10 to 15% PEC from C3H/HeJ mice resulted in undetectable migration inhibition at any MIF dilution. In contrast to the usual lack of responsiveness of their macrophage to MIF, C3H/HeJ mice were able to produce MIK in response to PPD as well as their counterpart C3H/HeN mice after BCG sensitization. These results demonstrate that macrophages from C3H/HeJ and C57BL/10ScCR mice are unable to be inhibited in their in vitro migration of MIF (possibly being directly or indirectly influenced by a suppressor cell), whereas lymphoid cells from at least one of these strains, the C3H/HeJ mice, can produce MIF in response to antigenic stimulation.
The first isolation and characterization of a lymphokine, the human MIF (MSF), and the availability of a specific MIF (MSF)-antibody provide an opportunity to establish a new parameter for detection of cellular immune mechanisms in various clinical situations. The precise estimation of quantitative amounts of MIF by sensitive immunochemical techniques could gain new insights into the pathogenesis of a number of clinical disorders. In addition, the exact detection of quantitative amounts of MIF in body fluids could have prognostic value.
Conditions are selected for the killer induction during primary and secondary responses in the one-way MLC, stimulated by x-irradiated or killed allogenic lymphocytes. MIF is found in the MLC culture medium as a sharp peak on the 2nd or the 3rd day of the primary reaction, or as a plato from the 1st day of the secondary reaction. In contrast, the killers are shown to be induced much later reaching their maximum on the 5th and the 4th days, respectively. If heated, instead of irradiated, allogenic lymphocytes were used for stimulation of the primary MLC reaction, the MIF-producer kinetics was not changed, but the killer induction was found to be delayed.
When migration inhibitory factor (MIF) assay in vitro was conducted on the lymphokines (LKs), it was observed that the percentage of MIF activity was greatly increased from the 3rd to the 4th week postinfection. On the succeeding weeks there was a noticeable decrease in the MIF activity noted on the 8th week postinfection of Toxoplasma. MIF activity was examined at 1, 6, 12, 18, 24 and 48 hours in non-immune spleen cells as well as Toxoplasma immune spleen cells in the 2nd week after the final challenge inoculation. MIF activity in Toxoplasma immune spleen cells were 2, 21, 29, 54, 70 and 93 percentage, respectively. The MIF activity of hyperimmunized spleen cells produced an activity of approximately 50% at 18 hours as compared to the non-immune spleen cells. Characterization of the MIF was performed using Sephadex G-100 and DEAE Sephadex A 50. Two distinct peaks of MIF were identified and separated by Sephadex G-100 gel filtration, calculating molecular weights between 30,000 to 40,000 and 3,000 to 5,000, respectively. When the fast peak by Sephadex G-100 was eluted again in DEAE Sephadex A 50, the peak was separated into 4 units, all units showing MIF activity.
Pulmonary alveolar macrophages (PAM) were obtained by lavage from baboons exposed for 6 mo to 2 ppm NO2 for 8 h/d, 5 d/wk, and the response of these cells to autologous migration inhibitory factor (MIF) was determined. PAM from two of three antigen-sensitized, NO2-exposed animals failed to respond to MIF derived from antigen-stimulated autologous lymphocytes. Similarly, PAM from three of the four NO2-exposed animals had diminished responsiveness to MIF obtained by phytohemagglutinin stimulation of their own lymphocytes. The altered responsiveness resulted from an effect on the macrophages and not on the lymphocytes used to prepare the MIF, as shown by the normal blastogenic responsiveness of the lymphocytes and the normal activity of the MIF thus produced on guinea pig peritoneal macrophages. These results demonstrate that inhalation of 2 ppm NO2 may have important subtle effects on pulmonary cells, which may result in altered immune capabilities within the lung.