Lymphocyte Adoptive Transfers
No one knows which immune response(s) are important to include in HIV vaccines. ‘Protective’ immune responses that mediate protection from other diseases have been characterized using lymphocyte ‘adoptive transfer’ experiments in mice. The immune responses generated by vaccination are typically complex and include both T and B cell responses. To define which of these responses are important, subpopulations of cells (e.g., CD8+ T cells) are collected from immunized mice and infused into naive recipients. The recipient mice are then exposed to the pathogen. The ability of the transfered immune cells to protect against pathogen is assessed. These experiments require genetically matched donors and recipients. Because macaques are genetically diverse, adoptive transfers have not been possible in the past. Our discovery that Mauritian macaques have extremely simple genetics allows us adoptively transfer SIV-specific lymphocytes for the first time.
Mauritian macaques have only six combinations of MHC genes that must be matched for adoptive transfer experiments. For example, cells from an H1/H1 donor should theoretically be tolerated in an H1/H1 recipient:
In 2008, we tested this hypothesis for the first time. We showed that MHC-matched lymphocytes persist for weeks in macaques. Cells from mismatched animals are rapidly rejected and disappear from the blood. The donor cells are shown below in the small blue box inset at each timepoint. Notice that 5 minutes after infusion, donor cells are detected in all three recipients, but by 9 days they are only found in the MHC-matched recipient:
Now that we have a nonhuman primate model for adoptive transfer studies, a number of exciting studies are possible. We are currently immunizing macaques with attenuated SIV to determine whether lymphocytes from these animals can protect recipients from pathogenic SIV infection. We are developing tools to traffic adoptively transfered cells to the anatomic sites in the recipient where battles between the virus and immune system are waged. Lastly, we are exploring adoptive transfers of cells that have been optimized in vitro to effectively kill SIV, borrowing a concept that has shown enormous promise against cancer. Our adoptive transfer studies are funded by NIH NIAID and the International AIDS Vaccine Initiative.