Text Image: UM Medical School: Graduate Program in Immunology
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Marilia Cascalho, M.D., Ph.D.
Associate Professor of Surgery
Associate Professor of
Microbiology and Immunology

Research interests

1. Molecular mechanisms to generate and maintain B cell memory in health and disease, including immunodeficiencies and transplantation.

2. The means by which B cells and/or immunoglobulin diversify the T cell repertoire and how these mechanisms impact on T cell responses to microbes, tumors and transplantation.

3. Generation of diversity in health and disease. We study molecular mechanisms for the generation of diversity of immune receptors and interrogate how those mechanisms shape immune responses to mutable pathogens and/or tumors.

Our research investigates human subjects and novel experimental gene-targeted and conditional gene expression mouse models.

Current Research Activity

1. We have identified mouse genetic mutants with defective B cell memory. Current research focuses on studying the mechanisms by which such genes contribute to B cell memory in response to pathogens and transplants. We study B cell memory in response to vaccination in children with severe contractions of the T cell compartment owing to removal of the thymus and T cell depletion as a consequence of cardiac transplantation in infancy.

2. We have developed a prototype for a novel vaccine called the “mutable vaccine”. The “mutable vaccine” consists of a DNA fragment encoding a viral antigen which is made to mutate at a rate that approximates the rate of viral diversification in infected individuals. Because the “mutable vaccine” generates non pathogenic viral antigenic variants, inducing immunity over time, we predict that vaccinated individuals will effectively generate sterilizing immunity to infection with mutable organisms such as HIV, influenza or hepatitis C. Research in the laboratory tests immunity generated in animals vaccinated with the “mutable vaccine”.

3. We discovered that immunoglobulin diversity promotes the development of T cell receptor diversity by enhancing selection of T cells in the thymus and by promoting T cell survival in the periphery. We study the mechanisms by which immunoglobulin contributes to diversity of T cells in mutant mice with contractions of the B cell repertoire.

Selected Publications

Panarra A, Ferreira E, Cascalho M, Nobre G. Sensibilidade à nistatina de estirpes de Candida torulopsis glabrata isoladas de material clínico (Resistance to nystatin in clinical isolates of Candida torulopsis glabrata). Jornal do Médico 115:460-462, 1984.

Falcão LM, Clara JG, Cascalho M, Matias D, Mota E. Ruptura septal, post enfarte agudo do miocárdio (Septal rupture after acute myocardial infarct). Rev Port Cardiol 4:431-437, 1988.

Cascalho M, Falcão M, Matias D, Carvalho L, Vieira C, Pinho R, Clara G, Mota E. A propósito de um caso de golpe de calor (Heat stroke in a schizophrenic patient). Medicina e Cirurgia 9:95-98, 1989.

Cascalho M, Neves J, Vassal H, Rodrigues H, Bicho M. Redutase transmembranar nos glóbulos vermelhos em hemodialisados crónicos e sua relação com o metabolismo do ferro (Modulation of the transmembrane ferricyanide reductase in red blood cells of renal insufficient patients and in relation to the iron metabolism). Jornal das Ciências Médicas 154:329-339, 1990. Pfizer Honor Mention-1989, Lisbon.

Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, DeCamilli P. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347:151-156, 1990.

Cascalho M, Ma A, Lee S, Masat L, Wabl M. A quasi-monoclonal mouse. Science 272:1649-1652, 1996.

Masat L, Cascalho M, Wabl M. Loss of the 1 subunit of the sodium pump during lymphocyte differentiation. Eur J Immunol 26:2731-2735, 1996.

Cascalho M, Wong J, Wabl M. VH gene replacement in hyperselected B cells of the quasimonoclonal mouse. J Immunol 159:5795-5801, 1997.

Cascalho M, Wong J, Steinberg C, Wabl M. Mismatch repair co-opted by hypermutation. Science 279:1207-1210, 1998.

Wabl M, Cascalho M, Steinberg C. Hypermutation in antibody affinity maturation. Curr Opin Immunol 11:186-189, 1999.

Cascalho M, Martin DA, Wong J, Lam Q, Wabl M, Wu GE. A mouse with monoclonal primary immunoglobulin repertoire not further diversified by V-gene replacement. Dev Immunol 7:43-50, 1999.

Lopez-Macias C, Kalinke U, Cascalho M, Wabl M, Hengartner H, Zinkernagel RM, Lamarre A. Secondary rearrangements and hypermutation generate sufficient B cell diversity to mount protective antiviral immunoglobulin responses. J Exp Med 189:1791-1798, 1999.

Garcia De Vinuesa C, Gulbranson-Judge A, Khan M, O’Leary P, Cascalho M, Wabl M, Klaus GG, Owen MJ, MacLennan IC. Dendritic cells associated with plasmablast survival. Eur J Immunol 29:3712-3721, 1999.

Cascalho M, Wong J, Brown J, Jäck HM, Steinberg C, Wabl M. A B220-negative, CD19-negative population of B cells in the peripheral blood of quasimonoclonal mice. Int Immunol 12:29-35, 2000.

de Vinuesa CG, Cook MC, Ball J, Drew M, Sunners Y, Cascalho M, Wabl M, Klaus GG, MacLennan IC. Germinal centers without T cells. J Exp Med 191:485-494, 2000.

Erickson LD, Vogel LA, Cascalho M, Wong J, Wabl M, Durell BG, Noelle RJ. B cell immunopoiesis: visualizing the impact of CD40 engagement on the course of T cell-independent immune responses in an Ig transgenic system. Eur J Immunol 30:3121-3131, 2000.

Golub R, Martin D, Bertrand FE, Cascalho M, Wabl M, Wu GE. VH gene replacement in thymocytes. J Immunol 166:855-860, 2001.

Cascalho M, Platt JL. The immunological barrier to xenotransplantation. Immunity 14:437-446, 2001.

Cascalho M, Platt JL. Xenotransplantation and other means of organ replacement. Nat Rev Immunol 1:154-160, 2001.

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: 737-745, 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 109:613-620, 2002.

Magari M, Sawatari T, Kawano Y, Cascalho M, Wabl M, Kanayama N, Hikida M, Ohmori H. Contribution of light chain rearrangement in peripheral B cells to the generation of high affinity antibodies. Eur J Immunol 32:957-966, 2002.

Kanayama N, Kimoto T, Todo K, Nishikawa Y, Hikida M, Magari M, Cascalho M, Ohmori H. B cell selection and affinity maturation during an antibody response in the mouse with limited B cell diversity. J Immunol 169:6865-6874, 2002.

Keshavarzi S, Rietz C, Simões S, 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 MutL. Mol Cell Biol 23: 3320-3328, 2003.

Kojima H, Sitkovsky MV, Cascalho M. HIF-1 deficiency perturbs T and B cell functions. Curr Pharm Des 9:1827-1832, 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.

Kojima H, Jones BT, Chen J, Cascalho M, Sitkovsky MV. Hypoxia–inducible factor 1 alpha-deficient chimeric mice as a model to study abnormal B lymphocyte development and autoimmunity. Methods Enzymol 381:218-229, 2004.

João CM, Ogle BM, Gay-Rabinstein C, Platt JL, Cascalho M. B cell-dependent TCR diversification. J Immunol 172:4709-4716, 2004.

Ogle BM, Butters KA, Plummer TB, Ring KR, Knudsen BE, Litzow MR, Cascalho M, Platt JL. Spontaneous fusion of cells between species yields transdifferentiation and retroviral transfer in vivo. FASEB J 18:548-550, 2004.

Cascalho M, Ogle BM, Platt JL. Xenotransplantation and the future of renal replacement. J Am Soc Nephrol 15:1106-1112, 2004.

Ogle BM, Cascalho M, Platt JL. Fusion of approaches to the treatment of organ failure. Am J Transplant 4(Suppl. 6): 74-77, 2004.

Cascalho M, Ogle BM, Platt JL. New approaches to replacing failing organs. Transplant Proc 36:1629, 2004.

Cascalho M, Platt JL. B cell-dependent T cell development. Acta Paediatr 93(Supplement 445):52-53, 2004.

Cascalho M. Advantages and disadvantages of cytidine deamination. J Immunol 172:6513-6518, 2004.

Ward MW, Reina-San-Martin B, Olaru A, Minn K, Tamada K, Lau JS, Cascalho M, Chen L, Nussenzweig A, Livak F, Nussenzweig MC, Chen J. 53BP1 is required for class switch recombination. J Cell Biol 165:459-464, 2004.

Wu X, Khalpey Z, Cascalho M. Cellular physiology of mismatch repair. Curr Pharm Des 10:4121-4126, 2004.

Cascalho M, Platt JL. Basic mechanisms of humoral rejection. Pediatr Transplant 9:9-16, 2005.

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, Platt JL. New technologies for organ replacement and augmentation. Mayo Clin Proc 80:370-378, 2005.

Cascalho M, Ogle, B, Platt JL. Emerging strategies in kidney transplantation. In: Chronic Kidney Disease, Dialysis, and Transplantation. Pereira BJG, Sayegh M, Blake P, eds. Elsevier: Philadelphia (2005) pp. 750-758.

Ogle BM,
Cascalho M, Platt JL. Biological implications of cell fusion. Nat Rev Mol Cell Biol 6:567-575, 2005.

Cascalho M. B cell tolerance: lessons from transplantation. Curr Drug Targets Cardiovasc Haemetol Disord 5:271-275, 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.

Cascalho M, Platt JL. The immunologic barriers to replacing damaged organs. Curr Immunol Rev 2:65-72, 2006.

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 176:1962-1967, 2006.

Cascalho M, Platt JL. The future of organ replacement: needs, potential applications and obstacles to application. Transplant Proc 38:362-364, 2006.

Cascalho M, Platt JL. B cells and B cell products—helping to restore cellular immunity? Transfus Med Hemother 33:45-49, 2006.

Cascalho M, Ogle BM, Platt JL. The future of organ transplantation. Ann Transplant 11:44-47, 2006.

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 179:2282-2288, 2007.

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.

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.

Kirk AD, Baldwin WM,
Cascalho M, Chong AS, Sykes M, West LJ. American society of transplantation symposium on B cells in transplantation: harnessing humoral immunity from rodent models to clinical practice. Am J Transplant 7:1464-1470, 2007

Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, Campbell PM,
Cascalho M, Collins AB, Demetris AJ, Drachenberg CB, Gibson IW, Grimm PC, Haas M, Lerut E, Liapis H, Mannon RB, Marcus PB, Mengel M, Mihatsch MJ, Nankivell BJ, Nickeleit V, Papadimitriou JC, Platt JL, Randhawa P, Roberts I, Salinas-Madrigal L, Salomon DR, Seron D, Sheaff M, Weening JJ. Banff ’05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’). Am J Transplant 7:518-526, 2007.

Tang AH, Brunn GJ, Cascalho M, Platt JL. Endogenous pathway to SIRS, sepsis and related conditions. J Leukoc Biol 82:282-285, 2007.

Cascalho M, Platt JL. Novel functions of B cells. Crit 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.

Cascalho M, Platt JL. Challenges and potential of xenotransplantation. In: Clinical Immunology. 3rd ed. Rich RR, Shearer WT, Fleisher TA, Schroeder HW, Weyand C, Frew AJ, eds. St Louis: Elsevier (2008) pp. 1215-1222.

Cascalho M, Ogle BM, Platt JL. Organogenesis and cloning. In: Living Donor Organ Transplantation. Gruessner R, Benedetti E, eds. New York: McGraw-Hill (2008) pp. 769-772.

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 6:10-18, 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.

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.

Balin SJ, Platt JL, Cascalho M. Non Cognate Function of B cells in Transplantation, Transplant International 22:593-598, 2009.

Platt JL, Cascalho M, West LJ. Lessons From Cardiac Transplantation in Infancy. Pediatric Transplantation, 13:814-819, 2009.

Balin SJ, Cascalho M. The Rate of Mutation of a Single Gene. Nucleic Acids Research 38:1575-1582, 2010.

Bolduc A, Long E, Stapler D, Cascalho M, Tsubata T, Koni PA, Shimoda M. Constitutive CD40L Expression on B Cells Prematurely Terminates Germinal Center Response and Leads to Augmented Plasma Cell Production in T Cell Areas. Journal of Immunology 185:220-230, 2010.

Cascalho M, Platt JL. Emerging strategies in kidney transplantation. In: Chronic Kidney Disease, Dialysis, and Transplantation 3rd ed. Pereira BJG, Sayegh M, Blake P, eds. Philadelphia: Elsevier, In Press.

Platt JL, Cascalho M. Transplantation Immunology. In: Greenfield’s Surgery: Scientific Principles and Practice 5th ed. Mulholland M, Lillemoe K, Doherty G, Maier R, Upchurch G, Simeone D, eds. Philadelphia: Lippincott Williams &Wilkins, In Press.

Cascalho M, Koch CA, Platt JL. B cell tolerance and accommodation. In: Incompatible Solid Organ Transplantation. Segev DL and Montgomery RA, eds. Berlin: Springer-Verlag. In Press.

Platt JL, Cascalho M. An Introduction to Innate Immunity. Innate Immunity, Submitted.

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