The Pishesha Lab

A nanobody is only useful if you can find the right one and then reshape it to do a job the natural antibody was never built for. Our lab runs alpaca immunization campaigns and screening efforts to isolate nanobodies (VHH, or variable heavy domain of heavy chain) against targets of interest, chosen for their ability to recognize three-dimensional epitopes with the precision of a conventional antibody but the size, stability, and modifiability of a single-domain protein. From there, we apply protein engineering to convert these binders into therapeutic agents, immune modulators, and tools for biochemistry and immune imaging: fusing them to cytokines, toxins, or fluorophores, and tuning their valency and half-life for the application at hand. This discovery-to-engineering pipeline is the foundation the rest of the lab builds on, and it extends outward: beyond generating nanobodies for our own programs, we collaborate extensively within the Division of Immunology, across Boston Children's Hospital and Harvard Medical School, with labs across the Greater Boston area, and with partners worldwide.

Autoimmune disease is rarely a failure of the whole immune system; it's a failure of timing and location, where the wrong cells receive inflammatory cues at the wrong moment. Allergy is a failure of tolerance too, just aimed at a different target: instead of misreading self as threat, the immune system misreads a harmless antigen as one. Our lab develops nanobody-based strategies that deliver anti-inflammatory signals with cellular precision, directing them to specific immune cell populations at specific sites rather than suppressing immunity broadly. The goal is durable immune tolerance: a reset that sustainably counteracts the hyperactive immune environments underlying autoimmune and allergic disease, rather than a temporary dampening that fades once treatment stops. We test these strategies in preclinical mouse models of autoimmunity and allergy and, where possible, in patient-derived samples, so that what we learn about targeted tolerance can move toward therapies that quiet disease without leaving patients broadly immunosuppressed.

Every T cell response starts with a question most immunologists take for granted: what exactly is being shown, by which cell, and how did it get there. Our lab studies the machinery of antigen presentation and processing: how antigens are captured, processed, and loaded onto MHC for display to T cells, and how that pathway differs across cell types and disease contexts. Because nanobodies can be engineered to target specific antigen-presenting cell populations with high selectivity, they give us a way to probe and manipulate this pathway directly: delivering antigen to a defined presenting cell, tracking how it's processed, and testing how that shapes the resulting T cell response. This is the mechanistic layer underneath both of the other programs in the lab: you can't precisely suppress or enhance a T cell response without understanding how the antigen that drives it was presented in the first place.

​If precision can turn immunity down, the same tools should be able to turn it up. As a counterpoint to our tolerance work, our lab investigates nanobody-based strategies to strengthen immune responses: engineering how and where immune cells encounter activating signals, rather than simply adding more of them. In vaccine settings, this means shaping the kinetics and localization of immune stimulation to drive stronger, more durable protective responses. In cancer, many tumors persist not because the immune system can't attack them, but because the tumor microenvironment actively suppresses the response, so we develop nanobody tools designed to reverse that suppression and restore an effective anti-tumor immune attack. Studying suppression and enhancement side by side gives us a single engineering framework for immunity that can be pointed in either direction, on demand.