Marilia Cascalho was educated in medicine (M.D., University of Lisbon) and in genetics, molecular biology and immunology (Ph.D. UCSF). She completed a post-doctoral fellowship at the Hagedorn Research Institute (Denmark) and UCSF where, supported by the JDF she identified the antigen targeted by immunity in type 1 diabetes. Dr. Cascalho pursued further training with Dr. Matthias Wabl at UCSF during which she engineered the first VDJ knock-in mice (the Quasi-Monoclonal Mouse) and discovered the novel concept that DNA repair actually engenders genomic plasticity in somatic hypermutation. Her research in this area led to her receipt of the coveted Science Magazine Prize for Young Investigators. In her first faculty appointment (Mayo Clinic, Rochester), Dr. Cascalho found unexpectedly that the B cell antibody repertoire diversity is necessary for positive selection of diverse T cells in the thymus and for the development and function of T cell memory. At the Mayo Clinic, her team found that a receptor of B and T cells, the Transmembrane Activator and CAML Interactor (TACI) is necessary for B cell differentiation into plasma cells providing a mechanism for how loss of function and dominant-negative alleles n may contribute to Common Variable Immune Deficiency (CVID) may cause decreased hypogammaglobulinemia and IgA-deficiency.
This work was supported by two NIH grants and a Gates Foundation grant. In 2008, Dr. Cascalho moved to the University of Michigan where she was supported by multiple NIH grants. Realizing that TACI variants known to impair receptor function are retained in populations and frequent in the healthy Dr. Cascalho proposed that the variants provide some advantage. Following this lead, the team found indeed that dominant-negative variants of TACI induce resistance to certain enterobacterial infections by controlling the development of virulence. Cascalho and colleagues also found that the advantages in host defense come at a cost of highly inflammatory responses that are deleterious in other settings such as transplantation, certain viral infections and in auto-immunity. In 2024, Dr. Cascalho was recruited to serve as Vice Chair of Research in the Department of Pathology CWRU, where she will hold the Richard J. Fasenmyer Chair in Immunopathogenesis.
The research has eventuated in disclosures and patents, papers in leading scientific journals (Nature, Science, Nature Medicine, Immunity, J Exp Med, J Clin Invest and others), the prestigious Science Award for young investigators and in grant awards from the NIH, DoD, Gates Foundation, State of Michigan and from the US-Israel Bi-National Science Foundation.
Research Information
Research Interests
Current research interests include the study of immunobiology of transplantation with the goal of developing strategies to induce resistance to immune-mediated injury, to explore mechanisms of immunopathogenesis by genetic susceptibility loci. Other interests include the development of novel immunotherapies including the development of a “mutable vaccine” that evolves in response to the host immunity with the goal of slowing viral evolution.
Research Projects
Donor-Specific B Cells in Transplantation.
The major goal of this project is to determine the properties of donor-specific B cells in recipients that maintain stable graft function and in those that undergo rejection. We found that donor-specific B cell intra-clonal diversification anticipate graft dysfunction and rejection. Research investigates mechanisms of antibody-mediated resistance or susceptibility to immune mediated injury.
A mutable vaccine to slow viral evolution.
The overall goal of the research is to determine protective immunity against mutable viruses generated by a novel vaccine strategy, the “mutable vaccine”. The mutable vaccine departs from canonical approach to vaccine design, which stresses a priori identification of variants. The mutable vaccine is a DNA vaccine that encodes a microbial antigen that diversifies in B cells undergoing somatic hypermutation. The variants are secreted from plasma cells and in turn evoke variant-specific immunity in anticipation of variants generated naturally. Current research tests these concepts but already it has revealed that the approach can anticipate viral gene variants that would emerge in human populations and generates cellular-mediated immunity that targets cells producing viral variants.
TNFRSF13B polymorphisms and immunity to transplantation and in host defense.
Dr. Cascalho and her colleagues discovered that the TNRSF13B (tumor necrosis receptor super-family 13B) gene encoding a receptor (also abbreviated as TACI, transmembrane activator and CAML interactor) expressed mostly by B cells is an immune-regulatory gene. TNFRSF13B is among the most polymorphic genes in humans and diversity at the locus is under positive selection. To resolve the conundrum of how non-functional alleles may benefit those who inherited them we proposed that diversity protects populations against unknown pathogens by assuring a wide array of immune responses that while disadvantageous in some individuals and in certain conditions, e.g. transplantation, will protect most against dissemination of microbes that evolved to explore the vulnerabilities of host defense. Current research tests how TACI variants modify immunity to transplants and in host defense.
C3d Immunotherapies to treat multiple myeloma and related conditions.
In a separate line of investigation, Dr. Cascalho and colleagues found that the fragment of the third component of complement (C3d) markedly boosts and accelerates cellular immunity slowing and sometimes reverting progression of tumors. C3d does so by vitiating tumor induced immunosuppression, i.e. the processes that impair immune responses to tumors. C3d induced cellular immunity is selective to cancer cells sparing healthy cells of the same lineage. Current research investigates how C3d enhances cellular immunity and efficacy against multiple myeloma, an incurable cancer and other cancers.
Awards and Honors
Publications
PATENTS
“Soluble C3d as an immunotherapy.” File# 2021-01179
“C3d cellular and acellular vaccines for the prevention and treatment of cancer.” PCT NO:US-01/34733- converted and awarded in 2021
“Mutable Vaccines.” US Patent No: US 7,776,321 B2
“Methods of assessing biologic diversity.” PCT NO: US04/12058 (Co-inventor)
“Methods for altering T cell diversity.” PCT NO: US05/07101 (Co-inventor)