We are involved in research projects to clarify risk factors for autoimmune thyroid disease with the expectation of identifying individuals within populations who are candidates for disease. We are actively determining the epitope-specific determinants of thyroglobulin that are associated with autoimmune thyroiditis. We have developed a panel of monoclonal antibodies to thyroglobulin and have identified regions of the molecule that patients recognize and may be associated with disease pathogenesis. A major interest is the investigation of the immunotoxic role of iodine in autoimmune thyroid disease. Epidemiologic and animal model evidence indicates that iodine may be an important factor in the development of thyroiditis in predisposed subjects. However, the pathogenetic mechanism is unknown. We are exploring the humoral and cell mediated immune response to variously iodinated thyroglobulins or their fragments in normal and patients with autoimmune thyroid disease. Identification of these individuals before the onset of disease will be useful to offset the biological deterioration caused by hormone imbalance (hypo- or hyper-thyroidism).

In addition our laboratory has an active program for the development of monoclonal antibodies to a variety of antigens in collaboration with other investigators.

Publications

Saboori AM, Rose NR, Yuhasz SC, Amzell M, Burek CL. Peptides of human thyroglobulin reactive with sera of patients with autoimmune thyroid disease. J. Immunol. 163:6244-6250, 1999.

Stone JH, Talor M, Stebbing J, Uhfelder ML, Rose NR, Carson KA, HellmannDB, Burek CL. Test characteristics of immunoflourscence and ELISA tests in856 consecutive patients with possible ANCA-associated conditions. ArthritisCare and Research. 13:424-434, 2000.

Butscher WG, Ladenson PW, Burek CL. Whole blood proliferation assay forautoimmune thyroid disease: comparison to density-gradient separated peripheral blood lymphocytes. Thyroid, 11:531-537, 2001.

Rose NR, Bonita R, Burek CL. Iodine: an environmental trigger ofthyroiditis. Autoimmunity Reviews 1:97-103, 2002.

Jeker LT, Hejazi M, Burek CL, Rose NR, Caturegli P. Mouse thyroidprimary culture. Biochem Biophys Res Commun. 1999 Apr 13;257(2):511-5.

Vali M, Rose NR, Caturegli P. Thyroglobulin as autoantigen:structure-function relationships. Rev Endocr Metab Disord. 2000Jan;1(1-2):69-77.

Mori-Aoki A, Pietrarelli M, Nakazato M, Caturegli P, Kohn LD, Suzuki K.Class II transactivator suppresses transcription of thyroid-specific genes.Biochem Biophys Res Commun. 2000 Nov 11;278(1):58-62.

Caturegli P, Hejazi M, Suzuki K, Dohan O, Carrasco N, Kohn LD, Rose NR. Hypothyroidism in transgenic mice expressing IFN-gamma in the thyroid. ProcNatl Acad Sci U S A. 2000 Feb 15;97(4):1719-24.

Ciháková D, Talor MV, Barin JG, Baldeviano GC, Fairweather D, Rose NR, Burek CL. Sex differences in a murine model of Sjögren's syndrome.Ann N Y Acad Sci. 2009 Sep;1173:378-83.

Cihakova D, Rose NR. Pathogenesis of myocarditis and dilated cardiomyopathy.Adv Immunol. 2008;99:95-114.

Cihakova D, Barin JG, Afanasyeva M, Kimura M, Fairweather D, Berg M, Talor MV, Baldeviano GC, Frisancho S, Gabrielson K, Bedja D, Rose NR. Interleukin-13 protects against experimental autoimmune myocarditis by regulating macrophage differentiation.Am J Pathol. 2008 May;172(5):1195-208. Epub 2008 Apr 10.

Ciháková D, Sharma RB, Fairweather D, Afanasyeva M, Rose NR. Animal models for autoimmune myocarditis and autoimmune thyroiditis.Methods Mol Med. 2004;102:175-93.

Cihakova D, Trebusak K, Heino M, Fadeyev V, Tiulpakov A, Battelino T, Tar A, Halász Z, Blümel P, Tawfik S, Krohn K, Lebl J, Peterson P. Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED.Hum Mutat. 2001 Sep;18(3):225-32.

We have tagged these molecules, and their chaperones in the ER, with green fluorescent protein, FP, tags and investigated their organization during assembly in the ER. Nascent class I molecules associate with the TAP complex for peptide loading. The diffusion of GFP-tagged class I molecules shows that they strongly associate with a very large TAP complex until they are peptide loaded. Once loaded, the molecules diffuse freely, but remain in the ER for some time. From these data we calculate that the TAP complex is very large, perhaps 100's of nm in diameter. We are presently investigating this question using GFP-tagged TAP1 molecules.

Recently we found a new chaperone for class I MHC molecules, the ER protein BAP31. Overexpression of the protein enhances surface expression of class I molecules, apparently by increasing the lifetime of MHC molecules. Resonance energy transfer measurements of proximity, as well as traditional immunoprecipitation experiments show BAP31 associated with class I MHC molecules during and after their peptide loading.

The surface organization of class I MHC molecules can affect their efficiency in antigen presentation. Class I MHC molecules on many cell types are clustered in patches of perhaps 25 molecules. We have developed methods for dispersing the clusters or for trapping them in membrane domains. Surprisingly, one method is depletion of cell cholesterol. Contrary to recent dogma on membrane lipid "rafts", we find that cholesterol depletion stabilizes the membrane skeleton and traps class I MHC molecules in clusters. These trapped molecules present antigen to effector T cells more efficiently than do the class I MHC molecules of unmodified target cells.

Publications

Kwik, J., Boyle, S., Fooksman, D. Margolis,L., Sheets, M.P. and Edidin, M. Membrane cholesterol, Lateral mobility and the PI(4,5)P2-dependent organization of cell actin. Proc. Natl. Acad. Sci. USA 100: 13694-13969 (2003).

Rocheleau, J.V., Edidin, M. and Piston, D.W. Intrasequence GFP in class I MHC molecules, a rigid probe for fluorescence anistropy measurements of the membrane environment. Biophys. J. 84: 4078-4086 (2003)

Edidin, M. The State of Lipid Rafts: from Model Membranes to Cells. Annu. Rev. Biophys. Biomolec. Struct. 32, 257-283 (2003).

Pentcheva, T., Spiliotis, E.T. and Edidin, M. Tapasin is retained in the endoplasmic reticulum by dynamic clustering and exclusion from endoplasmic reticulum exit sites. J. Immunol. 168: 1538-1541 (2002).

Spiliotis, E.T., H. Manley, M. Osorio, M. C. Zúñiga, and M. Edidin. Selective Export of MHC Class I Molecules from the ER after Their Dissociation from TAP. Immunity 13: 841-851 (2000)

Abdel Rahim A. Hamad, Abdiaziz S. Mohamood, Crystal J. Trujillo, Ching-Tai Huang, Emily Yuan and Jonathan Schneck. 2003. B220+ DN T cells suppress polyclonal T cell activation by a Fas-independent mechanism that involves inhibition of IL-2 production. J. Immunol. 171, 2421-2426

Abdel Rahim A. Hamad and Jonathan Schneck. 2001. Activation Induced Deathof T cell is Regulated by CD4 Coreceptor. Intern. Rev. Immunol. 20:1-12.

Abdel Rahim A. Hamad, Ananth Srikrishnan, Chris Breueren, Carl June, Drew Pardoll and Jonathan Schneck. 2000. Lack of Coreceptor Allows Survival of Chronically Stimulated CD4-CD8-B220+ T cells: Implications for Autoimmunity. J. Exp. Med. 193:1113-1121.

Abdel Rahim A. Hamad, Sean Oherrin, Ananth Sriskrishnan, Joane Bieler, Jonathan Schneck and Drew Pardoll. 1998. Potent T cell Activation with Dimeric MHC Class II- peptide complex: The Role of CD4 Molecule. J. Exp.Med. 188: 1633-1640.

Abdel Rahim Hamad, Philippa Marrack and John Kappler. 1997.Transcytosis of staphylococcal superantigen toxins. J. Exp.Med. 185:1447-1454

Miura, Y, Thoburn, CJ, Bright, EC, Phelps, ML, Shin, T, Matsui, EC, Matsui, WH, Arai, S, Fuchs, EJ, Vogelsang, GB, Jones, RJ, Hess, AD. Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood. 104(7):2187-2193, 2004.

Miura, Y, Thoburn, CJ, Bright, EC, Chen, W, Nakao, S, Hess, AD. Cytolytic effector mechanisms and gene expression in autologous graft-versus-host disease: Distinct roles of perforin and Fas ligand. Biology of Blood and Marrow Transplantation. 10:156-170, 2004.

Thoburn, CJ, Miura, Y, Bright, EC, Hess, AD. Functional divergence of antigen-specific T-lymphocyte responses in syngeneic graft-versus-host disease. Biology of Blood and Marrow Transplantation. 591-603, 2004.

Hess, AD, Thoburn, CJ, Miura, Y, Bright, EC. Functionally Divergent T lymphocyte responses induced by modification of a self-peptide from a tumor-associated antigen. Clinical Immunology. In press, 2004.

Hess, AD, Thoburn, CJ, Chen, W, Bright, EC. Unexpected T cell diversity in syngeneic graft-versus-host disease revealed by interaction with peptide-loaded soluble MHC class II molecules. Transplantation, 75:1361-1367, 2003.

Lee MT, Heller DS, Lambert WC, Bethel C. Cutaneous ciliated cyst with interspersed apocrine features presenting as a pilonidal cyst in a child. Pediatric Development Pathology. 2001 May-Jun;4(3):310-2.

Peter S. Amenta, Salim Hadad, Maria T Lee, Nicola Barnard, Jeanne Myers. Loss of types XV and XIX collagen precedes basement membrane invasion in ductal carcinoma of the female breast. Journal of Pathology 2003;199:298-308.

Olke M., U. Möhrle, D. Behringer, A. Lindemann, and A. Mackensen. Generation and purification of Melan-A-specific human CD8+ T cells in vitro for an adoptive transfer in tumor immunotherapy. Clin. Cancer Res., 6: 1997-2005, 2000

Mathias Oelke, Marcela V. Maus, Dominic Didiano, Carl June, Andreas Mackensen and Jonathan P. Schneck. Ex vivo induction and expansion of antigen-specific cytotoxic T cells by HLA-Ig coated artificial Antigen Presenting Cells. Nature Medicine 2003 May; 9(5):619-24

Mathias Oelke, Jonathan Schneck. HLA-Ig based artificial Antigen-presenting cells: Setting the terms of engagement. Journal of clinical immunology 2004; Vol 110/3 pp 243-251

Christine Krueger, Jonathan P. Schneck and Mathias Oelke. Quality and Quantity: New Strategies to improve immunotherapy of cancer. Trends in Molecular Medicine 2004 May;10(5):205-8.

Mathias Oelke and Jonathan Schneck. Immunotherapy with enhanced self immune cells. Discovery Medicine,4:203-207, 2004

1. Immunologic Tolerance - one of the important revelations in the area of cancer immunology is that the major mechanism by which tumors grow unchecked by the immune system is their ability to induce tolerance among mature T cells specific for tumor antigens. Our studies using transgenic mouse models have indicated that the same mechanisms that induce tolerance to peripheral tissue specific antigens likely are responsible for tolerance induction to tumor antigens. In particular, we have developed experimental evidence for the existence of a dedicated bone marrow derived 'tolerizing' antigen presenting cell (APC) responsible for processing and presenting cell tissue and tumor antigens to induce tolerance. We are currently using a combination of molecular and cellular approaches to identify the characteristics of the tolerizing APC and to understand the molecular basis for its capacity to induce antigen specific tolerance rather that activation of T cells.

2. Antigen Presentation - one of the cancer vaccine approaches that are being actively tested clinically is the vaccination with tumor cells transduced with the GM-CSF gene. These vaccines appear to be particularly potent because of the ability of the locally produced GM-CSF to activate the differentiation of bone marrow progenitors into dendritic cells. Using subtractive library approaches, we have been in the process of mapping out genes unique to dendritic cells that mediate their potent T cell stimulatory capacity. We are also defining cellular pathways by which exogenous antigens endocytosed by dendritic cell progenitors can enter the MHC class I processing pathway. Understanding these aspects of dendritic cell biology is central to the development of newer generations of more potent vaccines for both cancer as well as infectious diseases.

3. Definition of Immunodominant and Immunorelevant Tumor Antigens -Ultimately, we wish to define the biological and biochemical rules that determine which antigens are dominant targets for immune responses. We are currently using genomic approaches to rapidly screen for genes encoding antigens recognized by tumor specific T cells. In animal tumor models in which we have defined such antigens, we are studying the correlation between binding and physical properties of altered peptide ligands in vitro and immunogenicity in vivo.

4. Dissection of Immunologic Effector Pathways -Our studies on GM-CSF gene modified tumor vaccines have led to the identification of novel effect or pathways in tumor immunity. Besides the classical CTL response, we have found that activation of the eosinophils and activation of macrophages to produce NO and superoxides are critical pathways of tumor killing. Using in vitro systems for the chemical generation of these mediators, we have been defining molecular pathways by which these mediators specifically induce apoptosis in tumor cells. Ultimate definition of these effector pathways should lead to an understanding of how different antitumor agents can be utilized in synergy to effect enhanced antitumor immune responses. Relative to these immunologic effect or mechanisms, we are engineering new generations of targeted vectors, which will carry biologically active genes directly to tumors in vivo with the idea of inducing a cascade of apoptotic responses.

Huang AYC, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll DM, Levitsky H.Role of bone marrow derived cells in presenting MHC class I-restrictedtumor antigens. Science 264:961-965, 1994.

Huang AYC, Bruce AT, Pardoll DM, Levitsky HI. In vivo cross-priming of MHCclass I-restricted antigens requires the TAP transporter. Immunity 4:349-355, 1996.

Huang AYC, Gulden PH, Woods AS, Thomas MC, Tong CD, Wang W, Engelhard VH,Pasternack G, Cotter R, Hunt D, Pardoll DM, Jaffee EM. The immunodominantmajor histocompatibility complex class I-restricted antigen of a murine colontumor derives from an endogenous retroviral gene product. Proc Natl Acad Sci(USA) 93:9730-9735, 1996.

Adler AJ, Marsh DW, Yochum GS, Guzzo JL, Nigam A, Nelson WG, PardollDM. CD4+T cell tolerance to parenchymal self-antigens requirespresentation by bone marrow-derived antigen-presenting cells. J Exp Med187:1555-1564, 1998.

Afanasyeva M, Georgakopoulos D, Belardi DF, Bedja D, Fairweather D, Wang Y, Kaya Z, Gabrielson KL, Rodriguez ER, Caturegli P, Kass DA, ROSE NR. 2005. Impaired up-regulation of CD25 on CD4+ T cells in IFN-γ knockout mice is associated with progression of myocarditis to heart failure. Proc Natl Acad Sci 102:180-185.

Guler ML, Ligons DL, Wang Y, Bianco M, Broman KW, ROSE NR. 2005. Two autoimmune diabetes loci influencing T cell apoptosis control susceptibility to experimental autoimmune myocarditis. J Immunol 174:2167-2173.

Sharma RB, Alegria JD, Talor MV, ROSE NR, Caturegli P, Burek CL. 2005. Iodine and IFN-gamma synergistically enhance intercellular adhesion molecule 1 expression on NOD>H2h4 mouse thyrocytes. J Immunol 174:7740-7745.

Caturegli P, Newschaffer C, Olivi A, Pomper MG, Burger PC, ROSE NR. 2005.Autoimmune hypophysitis. Endocr Rev 26(5):599-614.

Several recent studies demonstrate that a potential for T cell autoreactivity resides in the immunological non-equivalency of different areas of self-molecules, since self-tolerance is only induced to efficiently presented, dominant epitopes, but not to cryptic ones. Thus, potentially autoreactive T cells that have not previously encountered the cryptic self still exist. As determinant dominance is influenced by protein structure, circumstances that change the molecular context of epitopes (e.g. novel cleavage, altered conformation or tertiary structure) may permit the efficient presentation of previously cryptic determinants, thereby breaking T cell tolerance. The unique autoantibody response observed in different autoimmune diseases may therefore be viewed as the long-lived immunologic memory of the altered circumstances that revealed this cryptic structure. We have found these antibodies to be useful probes with which to search for the initial perturbed state. Our laboratory uses the autoantibodies elaborated in systemic lupus erythematosus (SLE), inflammatory myositis, Sjogren syndrome, and scleroderma to search for circumstances which might reveal cryptic structure, by searching for mechanisms that underlie the clustered targeting of autoantigens in different autoimmune diseases. In initial studies that focused on lupus autoantigens, we observed that these autoantigens cluster and become concentrated in the surface blebs of apoptotic cells, where several of these molecules are specifically cleaved by proteases of the caspase family, potentially revealing cryptic determinants. Further studies have shown that these autoantigens are also cleaved by granzyne B duringCTL-induced apoptosis, generating unique fragments not observed during any other form of cell death. Our current studies focus on the cell biology and biochemistry of autoantigen clustering during cell damage and death, and the relevance of these novel changes to the immunogenicity of these molecules.

Publications

Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in systemiclupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 179:1317-1330, 1994.

Andracle F, Roy S, Nicholson D, Thornberry N, Rosen A, Casciola-RosenL. Granzyne B directly and efficiently cleaves several downstream caspasesubstrates: Implications for CTL-induced apoptosis. Immunity 8:451-460, 1998.

Casciola-Rosen L, Andrade F, Ulanet D, Wong WB and Rosen A. Cleavage by granzyme B is strongly predictive of autoantigen status: Implications for initiation of autoimmunity. J Exp Med 190:815-825, 1999.

Andrade F, Bull HG, Thornberry NA, Ketner GW, Casciola-Rosen LA, Rosen A. Adenovirus L4-100K assembly protein is a granzyme B substrate that potently inhibits granzyme B-mediated cell death. Immunity 14:751-761,2001. (See comments J Cell Biol 154:14, 2001).

Ulanet DB, Torbenson M, Dang CV, Casciola-Rosen L, Rosen A. Unique conformation of cancer autoantigen B23 in hepatoma: A mechanism for specificity in the autoimmune response. Proc. Natl. Acad. Sci. 100:12361-12366, 2003.

In addition, we study biophysical factors that contribute to the formation of the MHC-peptide complexes. We have shown that binding of peptides to MHC class II molecules is complex and involves multiple kinetic steps and conformational intermediates. Binding of different peptides to MHC class II induces different conformations. The conformational difference in MHC II-peptide complexes are physiologically significant as they are the basis for peptide editing by HLA-DM, an accessory molecule in antigen processing that has a critical role in capture and selective retention of antigenic peptides for T cell activation. We utilize Surface Plasmon Resonance, fluorescence and gel-based assays as well as other methods in protein chemistry for the study of molecular interactions.

Publications

Sadegh-Nasseri, S., L.J. Stern, D.C. Wiley, and R.N. Germain. 1994. Specific low affinity peptide binding precedes stable complex formation and preserves the function of MHC class II molecules. Nature. 370:647-650. Natarajan, S.K., M. Assadi, and S. Sadegh-Nasseri. 1999. Stable peptide binding to MHC class II molecules is rapid and is determined by a receptive conformation shaped by prior association of low affinity peptides. The Journal of Immunology. 162:4030-4036.

Chou, C.-L., and S. Sadegh-Nasseri. 2000. HLA-DM Recognizes the Flexible Conformation of Major Histocompatibility Complex Class II. The Journal of Experimental Medicine. 192:1697-1706.

Mirshahidi, S, C-T. Huang and S. Sadegh-Nasseri. 2001 Anergy in peripheral memory CD4(+) T cells induced by low avidity engagement of T cell receptor. The Journal of Experimental Medicine. 194(6):719-731.

Mirshahidi, S, L.C Korb Ferris & S. Sadegh-Nasseri. 2004. The Magnitude of TCR Engagement Is a Critical Predictor of T Cell Anergy or Activation. The Journal of Immunology. 172: 5346–5355.21.

Greten TF, Slansky JE, Kubota R, Soldan SS, Jaffee EM, Leist TP, PardollDM, Jacobson S, Schneck JP. Direct visualization of antigen-specific T cells: HTLV-1 Tax11-19 specific CD8+ T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients. Proc Natl Acad Sci(USA) 95:7568-7573, 1998.

Fahmy, T., Bieler, J.G., Edidin, M., and Schneck, J.P. Increased Tc Ravidity after T cell activation: A mechanism for sensing low density antigen. Immunity 14, 135-143, 2001, Cover Article.

Hamad AR, Srikrishnan A, Mirmonsef P, Broeren CP, June CH, Pardoll D, Schneck JP. Lack of coreceptor allows survival of chronically stimulated double-negative alpha/beta T cells: implications for autoimmunity. J Exp Med. 2001 May 21;193(10):1113-21.

Brehm MA, Pinto AK, Daniels KA, Schneck JP, Welsh RM, Selin LK. T cell immunodominance and maintenance of memory regulated by unexpectedly cross-reactive pathogens. Nat Immunol. 2002 Jul;3(7):627-34.

A second area of interest in our laboratory is the role of the mucosal immune compartment in the response against enteric gram-negative pathogens such as S. typhimurium. This interest is driven not only because these bacteria cause significant acute disease but also due to the etiological link between infection with Salmonella and related species with the development of chronic autoimmune disease. Our studies have identified a new subset of T cells residing within the epithelial barrier that expand following infection. Current efforts are focused on understanding the recognition properties and effector function of this T cell subset and determining if an analogous population exists in the human mucosa.

Lastly, we have initiated a proteomics based approach to identify autoimmune targets in the seronegative spondyloarthropathies, a set of rheumatological diseases for which we have little information as to the antigens that are involved in the initiation and/or progression of disease. It is our hypothesis that the identification of such targets will not only provide needed disease associated biomarkers, but also yield insights into the pathophysiology of disease.

Publications

Soloski, M.J., and Metcalf, E.M. (2001). The Involvement of Class I Molecules in the Host Response with Salmonella and its Relevance to Autoimmunity. Microbes and Infection 14:15:1249-1259.

Davies, A., Ramirez, S., Liang, B., Aldrich, C., Lemonnier, F., Jiang, H., Cotter, R. and Soloski, M.J., (2003) A Peptide from Heat Shock Protein 60 is the Dominant Peptide bound to Qa-1 in the absence of the MHC Class Ia Leader Sequence Peptide Qdm. J. Immunol. 170:5027-5033.

Lo, Wei-Feng, Dunn,C.C., Ong, H., Metcalf S.S. and Soloski, M.J., (2004). Bacterial and Host Factors Involved in the MHC class Ib-Restricted-Restricted Presentation of Salmonella Hsp 60: A Novel Pathway. Infection and Immunity 72:2843-2849

Davies, A. S. Lopez-Briones, H. Ong, C. O’Neil-Marshall, F.A. Lemonnier, K. Nagaraju, E. S. Metcalf, and Soloski, M.J., (2004) Infection Induced Expansion of A MHC Class Ib Dependent Intestinal Intraepithelial gamma/delta T Cell Subset. J. Immunol 172:6828-6837

In vitro studies suggest that alloantibodies manifest their effect directly and indirectly. By cross-linking class I MHC molecules on the surface of endothelial cells and smooth muscle cells, alloantibodies can stimulate the synthesis of growth factors (TGF-beta, PDGF and FGF) and secretion of monocyte chemotactic protein-1 (MCP-1). Macrophages can be activated by antibody and complement through Fc and complement receptors. Fc-gamma-Rs, which are expressed on a wide variety of hematopoeitic cells, including macrophages, monocytes and NK cells, link cellular and humoral immunity by bridging the antibody specificity to effector cells. Activated macrophages can produce TNF-alpha, IL-1, IL-6, which in turn can augment endothelial cell activation. Using immunoglobulin and complement knock out mice, I established models to test the mechanisms by which alloantibodies and complement are critical to the process of acute cardiac rejection and pathogenesis of vascular lesions.

Publications

Wasowska, B. A., K. J. Weider, W. W. Hancock, X. X. Zheng, B. Berse, J.Binder, T. B. Strom, and J. W. Kupiec-Weglinski. 1996. Cytokine and alloantibody networks in long term cardiac allografts in rat recipients treated with rapamycin. J Immunol, 156:395-404.

Qian, Z., B. A. Wasowska, E. Behrens, D. L. Cangello, J. R. Brody, S. S.Kadkol, L. Horwitz, J. Liu, C. Lowenstein, A. D. Hess, F. Sanfilippo, and W.M. Baldwin, III. 1999. C6 produced by macrophages contributes to cardiac allograft rejection. Am J Pathol, 155:1293-302.

Wasowska, B. A., Z. Qian, D. L. Cangello, E. Behrens, K. Van Tran, J.Layton, F. Sanfilippo, and W. M. Baldwin, III. 2001. Passive transfer of alloantibodies restores acute cardiac rejection in IgKO mice. Transplantation, 71:727-36.

Nakashima S, Qian Z, Rahimi S, Wasowska BA, Baldwin WM 3rd. 2002. Membrane attack complex contributes to destruction of vascular integrity in acute lung allograft rejection. J Immunol,169:4620-7

Rahimi S, Qian Z, Layton J, Fox-Talbot K, Baldwin WM 3rd, Wasowska BA. 2004. Non-complement- and complement-activating antibodies synergize to cause rejection of cardiac allografts. Am J Transplant, 4:326-34.