Recombinant human migration inhibitory factor has adjuvant activity.
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Biomedical subjects
L M Pozzi
Publications and source records attributed to L M Pozzi.
A point mutation in the human cytomegalovirus DNA polymerase gene confers resistance to ganciclovir and phosphonylmethoxyalkyl derivatives.
Ganciclovir-resistant mutant 759rD100 derived from human cytomegalovirus strain AD169 contains two resistance mutations, one of which is in the UL97 gene and results in decreased ganciclovir phosphorylation in infected cells [V. Sullivan, C. L. Talarico, S. C. Stanat, M. Davis, D. M. Coen, and K. K. Biron, Nature (London) 358:162-164, 1992]. In the present study, we mapped the second mutation to a 4.1-kb DNA fragment containing the DNA polymerase gene and showed that it confers ganciclovir resistance without impairing phosphorylation. Sequence analysis of the 4.1-kb region revealed a single nucleotide change that resulted in a glycine-to-alanine substitution at position 987 within conserved region V of the DNA polymerase. Recombinant viruses constructed to contain the DNA polymerase mutation but not the phosphorylation defect displayed intermediate resistance (4- to 6-fold) to ganciclovir relative to the original mutant 759rD100 (22-fold); the recombinant viruses also displayed resistance to ganciclovir cyclic phosphate (7-fold), 1-(dihydroxy-2-propoxymethyl)-cytosine (12-fold), and the phosphonylmethoxyalkyl derivatives (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (8- to 10-fold). However, the recombinant viruses remained susceptible to certain related compounds. These results imply that the human cytomegalovirus DNA polymerase is a selective target for the antiviral activities of ganciclovir, certain of its derivatives and phosphonomethoxyalkyl derivatives; support a role for region V in substrate recognition; and suggest the possibility of clinical resistance of human cytomegalovirus to these compounds because of polymerase mutations.
Amino Acid Sequence↗
Recombinant human migration inhibitory factor has adjuvant activity.
Recombinant human migration inhibitory factor (MIF), isolated through functional expression cloning in COS-1 cells, up-regulates expression of genes encoding HLA-DR and interleukin 1 beta (IL-1 beta) and elaboration of IL-1 beta by human monocyte-derived macrophages. Administration of soluble bovine serum albumin or human immunodeficiency virus 120-kDa glycoprotein (HIV gp120) to mice in the presence of recombinant MIF together with incomplete Freund's adjuvant induced a strong T-cell proliferative response comparable to that of complete Freund's adjuvant. Recombinant MIF also increased antibody production, especially of IgG1 and IgM, in mice. Taken together, these results indicate that recombinant MIF may be useful as an adjuvant in the development of vaccines.
Adjuvants, Immunologic↗
Human recombinant migration inhibitory factor activates human macrophages to kill Leishmania donovani.
A recombinant form of the first lymphokine to be discovered, migration inhibitory factor (rMIF) was obtained from COS-1 cells transfected with a cDNA library from a human T cell hybridoma (6). rMIF has an amino acid sequence unrelated to that of any known protein. To learn more about the biology of MIF, we tested its ability to effect the survival of Leishmania donovani in macrophages. We found that rMIF activates blood monocyte-derived macrophages in vitro to suppress the growth of and kill these intracellular parasites. The anti-leishmanial effect (ranging from 50 to 77% reduction of parasites) is maximal when macrophages have been incubated with rMIF 48 to 72 h before infection and is similar to that seen with macrophages activated by IFN-gamma. Of interest, whereas the activation of human macrophages by IFN-gamma is inhibited by IL-4 and not enhanced by LPS, the activation by rMIF is enhanced by LPS but is not inhibited by IL-4. The data presented here demonstrate that rMIF is a potent activator of macrophages and is likely to be critical in cell-mediated immune host defenses.
Animals↗