Delivery of MUC1 mucin peptide by Poly(d,l-lactic-co-glycolic acid) microspheres induces type 1 T helper immune responses.

Synthetic peptides corresponding to the variable tandem repeat domain of the cancer-associated antigen MUC1 mucin are candidates for cancer vaccines. In our investigation mice were immunized via subcutaneous injection with poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres containing a MUC1 mucin peptide. It was hypothesized that microencapsulation of the MUC1 mucin peptide would prime for antigen-specific Th1 responses while avoiding the need for traditional adjuvants and carrier proteins. Furthermore, an immunomodulator, monophosphoryl lipid A (MPLA), was incorporated into the peptide-loaded PLGA microspheres based on its ability to enhance Th1 responses. The results revealed T cell specific immune responses. The cytokine secretion profiles of the T cells consisted of high levels of interferon-gamma with undetectable levels of interleukin-4 and interleukin-10. Moreover, incorporation of MPLA in the MUC1 peptide-loaded PLGA microspheres resulted in an increase in interferon-gamma production. The antibody response was negative for IgM and IgG in the absence of MPLA; however, in the presence of MPLA antibody production was negative for IgM with a minimal IgG response consisting of IgG2a, IgG2b, and IgG3. Based on the antibody and cytokine profiles, it was concluded that MUC1 mucin peptide-loaded PLGA microspheres are capable of eliciting specific Th1 responses, which may be enhanced through the use of MPLA.

Use of a liposome antigen delivery system to alter immune responses in vivo.

It has been reported that a certain peptide encompassing residues 129-140 of the hepatitis B virus core antigen (HBcAg) leads to a Th2-type response in C57BL/10 mice. We postulated that by formulating the peptide in liposomes along with an immune modulator known as MPLA the immune response could be directed toward a Th1-type response. If these liposomes could deliver the peptide along with MPLA to antigen presenting cells, then the immune response generated could be polarized to a Th1 response. The type of immune response initiated after immunization with the peptide HBcAg (126-140) in different formulations was determined by an ex vivo T cell proliferation assay and by analysis of the cytokine profile of the proliferating T cells. A group of C57BL/6 mice immunized with peptide plus MPLA in a liposome formulation displayed a strong T cell proliferative response. The T cell subset was identified as Th1 based on the cytokine profile. The cytokine profiles showed significant production of interferon-gamma (IFN-gamma, a Th1-type cytokine) and extremely low levels of interleukin-4 (IL-4, a Th2-type cytokine). The control group of C57BL/6 mice immunized with peptide plus alum showed a very low level of T cell proliferation, and no increase was seen in IFN-gamma or IL-4 production. These data signify that a Th1-type response occurred in mice treated with peptide in a liposome formulation but not in mice treated with the control formulation.