Administrative Contact
Stephanie La Vigne (Transplant Surgery)
Biography
I am fluent in Portuguese, speak and read French and Spanish albeit not fluently.
My interests outside Science are the Arts and in particular Music. I play the modern flute and I am a student of the baroque flute.
Appointments
Areas of Interest
I am educated in medicine and have a Ph.D. and training in basic sciences (genetics, molecular biology and immunology). My current research resides in fields of transplantation immunology, host-defense, immunotherapies, genetics and vaccine design. The research has eventuated in a number of 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, (currently, 5 R01 and 2 R21), DoD, Gates Foundation, State of Michigan and from the US-Israel Bi-National Science Foundation.
My colleagues and I have made several seminal discoveries. (1) My interest on B cell biology was sparked by my early work on molecular mechanisms of immunoglobulin gene recombination and mutation and led to the discovery that DNA mismatch repair drives B cell Ig gene hypermutation. This discovery inspired the approach to a mutable-antigen mouse platform to anticipate immune-driven evolution of antigens from mutable viruses. (2) We established that B cell and immunoglobulin diversity promote T cell development and the establishment of a diverse antigen receptor (TCR) repertoire. This observation led to current research directed at understanding how functions of B cells impact cellular immunity and regulation of immune responses in human health and disease. (3) We discovered that the TNRSF13B gene encoding a receptor (also abbreviated as TACI) expressed mostly by B cells is an immune-regulatory gene. TNRSF13B is among the most diverse gene in humans and vertebrates, TNRSF13B defines the type and intensity of innate and adaptive B cell responses, the interactions between B and T cells and in doing so also controls complement activation. Thus, while TNFRSF13B low-functioning alleles are beneficial in host defense blocking microbial transmission and epidemic spread, these same polymorphisms increase inflammation in part owing to decreasing control of complement activation. These findings suggested that TNFRSF13B gene 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. (4) We found that the fragment d 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.
Expertise areas: B cell responses to transplantation and in host defense; Genomic determinants of immunity; Immunoglobulin gene diversification; Immunotherapies.
Honors & Awards
Society of University Surgeons (2010).
Science Prize for Young Investigators (1999).
Praxis XXI Post-Doctoral Fellowship (1999).
Leukemia Research Foundation Fellowship (1998);.
Praxis XXI Fellowship (1995).
Fundação Calouste Gulbenkian Fellowship (1994).
Junta Nacional de Investigação Científica e Tecnológica Fellowship (1991-1994);.
Juvenile Diabetes Foundation Fellowship (1989-1991).
Pfizer Honorable Mention (1990).
Instituto Nacional de Investigação Científica Fellowship (1989).
Grants
Title: Donor-specific B cells in Transplantation
Major Goals: To determine the properties of donor-specific B cells in recipients that maintain stable graft function and in those that undergo rejection.
Project Number: NIH R01 AI 151588 (UM ID AWD016359)
TNFRSF13B polymorphisms and immunity to transplantation
Major Goals: 1: To identify genomic polymorphisms of the TNFRSF13B gene that condition B cell responses and the propensity for rejection in kidney transplant recipients. 2: To trace the evolution of donor-specific B cell clones in subjects with and without TNFRSF13B polymorphisms and 3: To determine how select TNFRSF13B variants condition B cell responses
Project Number: 1-R01- AI 173950 (UM ID 22-PAF03896)
TNRSF13B polymorphisms and the control of innate B cell responses – a double edged sword
Major Goals: 1: To determine how tnfrsf13b controls infection and dissemination of C. rodentium 2: To determine how IgA induces C. rodentium virulence
Project Number: R21 AI 159219 (UM ID AWD017193)
A novel rabbit model for easy monoclonal antibody production
Major Goals: In the present project, we propose to gene edit the rabbit TACI gene with the goal to enhance the hybridoma efficiency in rabbits.
Project Number: R21 GM 140359 (UM ID AWD016242)
Engineering an immuno-isolating hydrogel for restoring ovarian endocrine function
Major Goals: The proposed research aims to restore ovarian endocrine function in young women with premature ovarian insufficiency by utilizing human xenogeneic implantation of ovarian tissue in immuno-isolating hydrogel-based capsule.
Project Number: R01 HD 104173 (UM ID AWD017628)
Ovarian allografts for restoration of endocrine function
Major Goals: 1) to investigate whether encapsulated human ovarian follicles activate, grow and mature in immunocompromised mice; and 2) to investigate whether encapsulated human ovarian follicles function in immune competent mice.
Project Number: UM ID AWD019558
Immuno-isolating capsule for delivery of cell-based therapy for restoration of ovarian endocrine function in adolescent Rhesus Macaques
Major Goals: In this study we will investigate the capability of encapsulated allogeneic ovarian tissue to initiate physiological puberty in adolescent non-human primates, and the longevity of graft function along with the dynamics of the recipient’s immune response to a single and repeated transplantations.
Project Number: 1 R01HD105018 01 A1 (UM ID 22-PAF02667)
Characterization of the mutable vaccine approach in a model of HIV-1
Major Goals: First testing in a pre-clinical model of a mutable vaccine strategy for HIV
Project Number: University of Michigan/Israel collaboration
A mutable vaccine approach for protection against highly mutable viruses
Major Goals: The overall goal of the research is to determine protective immunity against HIV generated by a novel vaccine strategy, the mutable vaccine. We will also adapt the technology to vaccinate against Influenza.
US-Israel Binational Science Foundation
Project Number: (UM ID #22-PAF02685)
Virus-Like Nanoparticles for Non-Capsid Antigen Delivery with Virus Structure/Functional Mimicry to Activate B Cell Immunity
Major Goals: In this proposal, we will generate in organic virus like nanoparticles (IVLNs) with three features of spiky peplomers of virus using four types of small antigens (peptides of anthrax and botulinum toxins, small molecule 4-hydroxy-3-nitrophenyl acetyl-hapten, HER2 peptides) to test our hypothesis.
Project Number: R01 AI154072 (UM ID AWD015612)
Published Articles or Reviews
Balin SJ, Cascalho M. The Rate of Mutation of a Single Gene. Nucleic Acids Research, doi: 10.1093/nar/gkp1119, 2009.
Platt JL, Cascalho M, West LJ. Lessons From Cardiac Transplantation in Infancy. Pediatric Transplantation, 13:814-819, 2009.
Balin SJ, Platt JL, Cascalho M. Non Cognate Function of B cells in Transplantation, Transplant International 22:593-598, 2009.
Cascalho M, Ogle BM, Razonable RR, West LJ, Platt JL. Cardiac transplantation in infancy: A model for dissecting immunological function. Journal of Paediatrics and Child Health 18 (Suppl 1):30-32, 2008.
Cascalho M, Platt JL. B cells diversify the T cell receptor repertoire. In: "Journal of Paediatrics and Child Health" in the Proceedings of the 3rd Joint Conference OPBG/Mayo. Journal of Paediatrics and Child Health 18 (Suppl 1):S14-S15, 2008.
Balin SJ, Platt JL, Cascalho M. New insights into the functions of B cells. Pediatr Transplant, 12:510-515, 2008.
Balin SJ, Ross TM, Platt JL, Cascalho M. HIV genes diversify in B cells. Curr HIV Res. 6:10-8.2008.
AbuAttieh M, Rebrovich M, Wettstein PJ, Vuk-Pavlovic Z, Limper AH, Platt JL, Cascalho M. Fitness of cell-mediated immunity independent of repertoire diversity. J Immunol 178:2950-2960, 2007.
Mantchev GT, Cortesão C, Rebrovich M, Cascalho M, Bram RJ. TACI is required for efficient plasma cell differentiation in response to T-independent type 2 antigens. J Immunol 179:1962-1967, 2007 (MC: Corresponding Author).
Geraldes P, Rebrovich M, Herrmann K, Wong J, Jäck H-M, Wabl M, Cascalho M. Ig heavy chain promotes mature B cell survival in the absence of light chain. J Immunol 179:1659-1668, 2007.
Cascalho M, Platt JL. Novel functions of B cells. Curr Rev Immunol 27:141-151, 2007.
Martin DA, Lu L, Cascalho M, Wu GE. Maintenance of surrogate light chain expression induces developmental delay in early B cell compartment. J Immunol 179:4996-5005, 2007.
Ogle, BM., West, LJ., Driscoll, DJ., Strome, SE., Razonable, RR., Paya, CV., Cascalho, M., Platt, JL. Effacing of the T cell compartment by cardiac transplantation in infancy. J Immunol 176(3):1962-1967, 2006.
Cascalho M, Platt JL. B cells and B cell products-helping to restore cellular immunity? Transfus Med Hemother 33(1):45-49, 2006.
Cascalho M, Platt JL. The immunologic barriers to replacing damaged organs. Curr Immunol Rev 2:65-72, 2006.
Wu X, Geraldes P, Platt JL, Cascalho M. The double-edged sword of activation-induced cytidine deaminase. J. Immunol 174:934-941, 2005.
Cascalho M. B cell tolerance: lessons from transplantation. Curr Drug Targets - Cardiovasc & Haematol Disord 5(3):271-5, 2005.
Cascalho M, Platt JL. Basic mechanisms of humoral rejection. Pediatr Transplantation 9:9-16, 2005.
Kanayama N, Cascalho M, Ohmori H. Analysis of marginal zone B cell development in the mouse with limited B cell diversity: role of the antigen receptor signals in the recruitment of B cells to the marginal zone. J Immunol 174:1438-1445, 2005.
Ogle BM, Cascalho M, Platt JL. Biological implications of cell fusion. Nat Rev Mol Cell Biol 6:567-575, 2005.
João CM, Ogle BM, Gay-Rabinstein C, Platt JL, Cascalho M. B cell-dependent TCR diversification. J Immunol 172(8):4709-4716, 2004.
Ogle BM, Butters KA, Plummer TB, Ring KR, Knudsen B, Litzow MR, Cascalho M, Platt JL. Spontaneous fusion of cells between disparate species yields transdifferentiation and retroviral DNA transfer in vivo. FASEB J 18:548-550, 2004.
Cascalho M. Advantages and disadvantages of cytidine deamination. J Immunol 172:6513-6518, 2004.
Keshavarzi S, Rietz C, Simões S, Wong J, Shih S, Platt JL, Wong J, Wabl M, Cascalho M. The possibility of B-cell-dependent T-cell development. Scand J Immunol 57:446-452, 2003.
Wu X, Platt JL, Cascalho M. Dimerization of MLH1 and PMS2 limits nuclear localization of MutLα. Mol Cell Biol 23: 3320-3328, 2003.
Kojima H, Sitkovsky MV, Cascalho M. HIF-1α deficiency perturbs T and B cell functions. Curr Pharm Des 9:1827-32, 2003.
Ogle BM, Cascalho M, Joao CM, Taylor W, West LJ, Platt JL. Direct measurement of lymphocyte receptor diversity. Nucleic Acids Res 31:e139, 2003.
O'Connor BP, Cascalho M, Noelle RJ. Short-lived and long-lived bone marrow plasma cells are derived from a novel precursor population. J Exp Med 195(6):737-45, 2002.
Erickson LD, Durell BG, Vogel LA, O'Connor BP, Cascalho M, Yasui T, Kikutani H, Noelle RJ. Short-circuiting long-lived humoral immunity by the heightened engagement of CD40. J Clin Invest 109(5):613-20, 2002.
Cascalho M, Platt JL. The immunological barrier to xenotransplantation. Immunity 14:437-446, 2001.
Cascalho M, Platt JL. Xenotransplantion and other means of organ replacement. Nature Reviews 1:154-160, 2001.
Vinuesa C, Cook M, Ball J, Drew M, Sunners Y, Cascalho M, Wabl M, Klaus G, MacLennan I. Germinal centres can form without T cells, but a failsafe mechanism prevents the emergence of autoreactive cells. J Exp Med 191:485-94, 2000.
Wabl M, Cascalho M, Steinberg C. Hypermutation in antibody affinity maturation. Curr Opin Immunol 11:186-189, 1999.
Lopez-Macías C, Kalinke U, Cascalho M, Wabl M, Hengartner H, Zinkernagel R M, Lamarre A. Secondary rearrangements and hypermutation generate sufficient B cell diversity to mount protective antiviral immunoglobulin responses. J Exp Med 189:1791-1798, 1999.
Cascalho M, Wong J, Steinberg C, Wabl M. Mismatch repair co-opted by hypermutation. Science 279:1207-1210, 1998.
Cascalho M, Wong J, Wabl M. VH gene replacement in hyperselected B cells of the quasi-monoclonal mouse. J Immunol 159:5795-5801, 1997.
Cascalho M, Ma A, Lee S, Masat L, Wabl M. A quasi-monoclonal mouse. Science 272:1649-1652, 1996.
