Immunomodulatory potential of hydrophobic analogs of Rigin and their role in providing protection against Plasmodium berghei infection in mice.
Here, we report the immunomodulating potential of N-palmitoyl-amino-ethyl-rigin amide (PR) and N-cholestanyl-amino-ethyl-rigin amide (CR), the two new structural analogs of rigin (an IgG-derived tetrapeptide). Their activity profiles are compared with native tuftsin (NT) and/or N-palmitoyl-amino-ethyl-tuftsin amide (PT) taken as positive control. To explore the possibility of their use as targeting molecules, they are incorporated into the liposome bilayer and, subsequently, interacted with macrophages in an in vitro study. The new analogs of rigin with the hydrophobicity introduced at the C-terminus are found to considerably improve both the cell-mediated and the humoral immune responses in mice. However, unlike tuftsin and its analog, which mainly activate polymorphonuclear leukocytes and macrophages, the rigin analogs appear to manifest their response more through lymphocytes. When administered prophylactically to a group of mice, at the dose of 100 micrograms/0.5 ml/mouse/day for 2 days (i.v.), followed by a challenge presented with 1 x 10(6) rbcs parasitised with Plasmodium berghei on day 0, substantial reduction in parasitaemia and rate of mortality is observed. This led to increase the median survival time (MST) of the treated group in comparison to the control group. The response is found to be more prominent in CR-treated mice possibly because of the presence of steroid moiety, which is likely to have more productive interaction with cell membranes. Incorporation of these peptides into the bilayer of liposomes does not alter the permeability behavior of vesicles and, in fact, enhances their uptake by the macrophages in an in vitro study. The effect, however, is dependent on both, the concentration of peptide liposomes and the time of incubation. Present study, thus, establishes the possible use of these analogs not only as adjuvant in chemotherapy, but also as a prophylactic supplement to boost the natural immune status. The activity response of rigin analogs is manifested through lymphocytes, they can also find use in the chemotherapy of diseases, like leishmaniasis, tuberculosis and leprosy, where macrophage activity is either tamed or impaired by pathogens.
Dutta
R C
RC
Division of Membrane Biology, Central Drug Research Institute, Lucknow 226 001, India. ranjna@iict.ap.nic.in
Puri
A
A
Anand
N
N
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D005029:Ethylenediamines / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008081:Liposomes; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008288:Malaria / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010962:Plasmodium berghei; D014405:Tuftsin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D005029:Ethylenediamines; D008081:Liposomes; C440775:N-cholestanyl-amino-ethyl-rigin amide; C440776:N-palmitoyl-amino-ethyl-rigin amide; D009842:Oligopeptides; C077747:tuftsin-M; D014405:Tuftsin