Ellen Heber-Katz

Last updated
Ellen Heber-Katz
HeberKatz Ellen.jpg
Born
Philadelphia, Pennsylvania, U.S
Alma mater University of Pennsylvania
University of Wisconsin Madison
Scientific career
FieldsImmunology, Microbiology
Institutions Lankenau Institute for Medical Research
The Wistar Institute

Ellen Heber-Katz is an American immunologist and regeneration biologist who works as a professor at Lankenau Institute for Medical Research (LIMR). [1] She discovered that the Murphy Roths Large (MRL) mouse strain can regenerate wounds without scarring and fully restore damaged tissue. [2] [3] [4] [5] [6] Her research focuses on immunology, regenerative medicine, and cancer. [7] In July 2015, she expanded her research to include studies funded by the National Cancer Institute (NCI) that investigate novel aspects of breast cancer causation. [8]

Education and career

Heber-Katz received her B.A. in microbiology and immunology in 1969. She received her M.S. in immunology in 1972 from the University of Wisconsin-Madison while studying with Robert E. Click. [9] Her M.S. thesis focused on the role of reducing agents as critical factors in cellular immune responses. [9] In 1976, she earned her Ph.D. in immunology from the University of Pennsylvania, studying with D.B. Wilson. [10]

In her thesis work, she showed that single T-cell subsets could respond to both histocompatibility antigens and environmental antigens, establishing the unity of these two branches of the immune response. She pursued postdoctoral studies at the National Institutes of Allergy and Infectious Diseases (NIAID) in the Laboratory of Immunology, under the immunologists E. Shevach, W.E. Paul, and R. Schwartz. While there, she established the first functional evidence for the formation of a molecular complex between a T-cell antigen and the MHC class Ia molecule, anticipating the crystal structure later determined for this fundamental molecular complex in T-cell biology. [11] [12]

At NIAID, Heber-Katz also conducted experiments that illuminated the molecular details involved in controlling interactions between T-cells and macrophages. [13] The experiment termed the "A/5R experiment" confirmed the Determinant Selection Hypothesis, which concerned the spatial relationships between the histocompatibility I-A and I-E molecules on the surface of antigen-presenting cells, the bound antigen and the recognition structure of the T-cell receptor, contributing to the fundamental understanding of how ‘foreign’ antigens activate the adaptive immune system in mammals. [14]

In 1976, Heber-Katz was appointed as the Assistant Professor at the Wistar Institute. In her viral studies, she developed a T-cell vaccine for the herpes virus HSV-2 that could protect subjects against lethal infection in the total absence of an antibody response. This proved for the first time that, by themselves, T-cells could protect against lethal viral infection. [15] In her autoimmune studies, she developed the “V Region Disease Hypothesis” in showing that the same T-cell receptor in mice and rats recognized different antigens to mediate different diseases. [16]

In 1995, during her investigations into how autoimmune disease arises, Heber-Katz discovered that two of the mouse strains she was using (MRL/LPR and MRL/MPJ) had an unusual ability to heal in a regenerative amphibian-like fashion rather than through a fibrotic response. [17] [18] This was shown first for ear hole closure but was extended to many organ systems such as the heart. Together with Dr. Robert K. Naviaux at the University of California at San Diego, an expert in mitochondrial physiology, Heber-Katz discovered that a key to non-scarring healing in the adult MRL mouse was activation of an embryonic metabolic pattern known as aerobic glycolysis, suggesting the types of molecules involved in this unusual healing response. [19] In particular, hypoxia-inducible factor-1a (HIF-1a) was identified as a critical molecule, based on the discovery that blocking its activity in MRL mice was sufficient to eliminate the regenerative response. [20]

She has investigated therapeutic strategies to activate this regenerative healing response with Phillip Messersmith, a biomaterials chemist at the University of California at Berkeley. [20] [21] An initial milestone was the creation of time-release hydrogel formulations of a prolyl hydroxylase inhibitor that, when delivered subdermally, confers regenerative healing to a normal mouse. She has obtained evidence of regenerative healing of chronic wounds and osteoporosis in aged mice using this experimental therapeutic approach. [22] With Dr. George Hajishengallis at the University of Pennsylvania School of Dentistry, the hydrogel drug formulation was shown to induce rapid and complete bone and soft tissue regrowth in a preclinical model of periodontal disease, characterized by tooth loss and jaw bone degeneration. [23]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

<span class="mw-page-title-main">Immune system</span> Biological system protecting an organism against disease

The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

<span class="mw-page-title-main">Immunology</span> Branch of medicine studying the immune system

Immunology is a branch of biology and medicine that covers the study of immune systems in all organisms.

<span class="mw-page-title-main">DNA vaccine</span> Vaccine containing DNA

A DNA vaccine is a type of vaccine that transfects a specific antigen-coding DNA sequence into the cells of an organism as a mechanism to induce an immune response.

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

<span class="mw-page-title-main">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

<span class="mw-page-title-main">Healing</span> Process of the restoration of health

With physical trauma or disease suffered by an organism, healing involves the repairing of damaged tissue(s), organs and the biological system as a whole and resumption of (normal) functioning. Medicine includes the process by which the cells in the body regenerate and repair to reduce the size of a damaged or necrotic area and replace it with new living tissue. The replacement can happen in two ways: by regeneration in which the necrotic cells are replaced by new cells that form "like" tissue as was originally there; or by repair in which injured tissue is replaced with scar tissue. Most organs will heal using a mixture of both mechanisms.

<span class="mw-page-title-main">Memory B cell</span> Cell of the adaptive immune system

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

<span class="mw-page-title-main">Interleukin 33</span> IL-33 induces helper T cells, mast cells, eosinophils and basophils to produce type 2 cytokines.

Interleukin 33 (IL-33) is a protein that in humans is encoded by the IL33 gene.

<span class="mw-page-title-main">CD86</span> Mammalian protein found in Homo sapiens

Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.

<span class="mw-page-title-main">Lankenau Institute for Medical Research</span>

Lankenau Institute for Medical Research (LIMR), founded in 1927, is a nonprofit, biomedical research institute located on the campus of Lankenau Medical Center in Wynnewood, Pennsylvania, serving as the research division of the Main Line Health System in suburban Philadelphia. LIMR focuses on studies of cancer, cardiovascular, autoimmune, gastrointestinal and other diseases. It houses a center for population health research.

Certain sites of the mammalian body have immune privilege, meaning they are able to tolerate the introduction of antigens without eliciting an inflammatory immune response. Tissue grafts are normally recognised as foreign antigens by the body and attacked by the immune system. However, in immune privileged sites, tissue grafts can survive for extended periods of time without rejection occurring. Immunologically privileged sites include:

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

Murphy Roths large (MRL/MpJ) is a strain of laboratory mouse developed in 1999 at The Wistar Institute in Philadelphia, Pennsylvania. Originally bred for autoimmune disease research, it was discovered to have remarkable tissue regeneration abilities.

MHC multimers are oligomeric forms of MHC molecules, designed to identify and isolate T-cells with high affinity to specific antigens amid a large group of unrelated T-cells. Multimers generally range in size from dimers to octamers; however, some companies use even higher quantities of MHC per multimer. Multimers may be used to display class 1 MHC, class 2 MHC, or nonclassical molecules from species such as monkeys, mice, and humans.

Mucosal-associated invariant T cells make up a subset of T cells in the immune system that display innate, effector-like qualities. In humans, MAIT cells are found in the blood, liver, lungs, and mucosa, defending against microbial activity and infection. The MHC class I-like protein, MR1, is responsible for presenting bacterially-produced vitamin B2 and B9 metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease, although definitive evidence is yet to be published.

Macrophage polarization is a process by which macrophages adopt different functional programs in response to the signals from their microenvironment. This ability is connected to their multiple roles in the organism: they are powerful effector cells of the innate immune system, but also important in removal of cellular debris, embryonic development and tissue repair.

<span class="mw-page-title-main">CD1b</span> Mammalian protein found in Homo sapiens

T-cell surface glycoprotein CD1b is a protein that in humans is encoded by the CD1B gene.

References

  1. ↑ "Ellen Heber-Katz, PhD - LIMR - Researcher Profile". LIMR. Retrieved 2016-04-02.
  2. ↑ Galatz, Leesa M.; Gerstenfeld, Louis; Heber-Katz, Ellen; Rodeo, Scott A. (2015). "Tendon regeneration and scar formation: The concept of scarless healing". Journal of Orthopaedic Research. 33 (6): 823–831. doi:10.1002/jor.22853. PMC   6084432 . PMID   25676657.
  3. ↑ Zhang, Yong (2015-06-03). "Drug-induced regeneration in adult mice | Science Translational Medicine". Science Translational Medicine. 7 (290): 290ra92. doi:10.1126/scitranslmed.3010228. PMC   4687906 . PMID   26041709.
  4. ↑ Gourevitch, D; Kossenkov, AV; Zhang, Y; Clark, L; Chang, C; Showe, LC; Heber-Katz, E (2015-09-28). "Inflammation and Its Correlates in Regenerative Wound Healing: An Alternate Perspective". Adv Wound Care (New Rochelle). 3 (9): 592–603. doi:10.1089/wound.2014.0528. PMC   4152783 . PMID   25207202.
  5. ↑ Edwards, RG (2015-09-28). "From embryonic stem cells to blastema and MRL mice". Reprod. Biomed. Online. 16 (3): 425–61. doi:10.1016/S1472-6483(10)60605-0. PMID   18339268.
  6. ↑ "Case Closed: A Fluky Finding Raises Hopes for Mending Wounds". Scientific American. Retrieved 2016-04-02.
  7. ↑ "From Immunity and Vaccines to Mammalian Regeneration". The Journal of Infectious Diseases . 212. 2015. Retrieved 2016-04-03.[ dead link ]
  8. ↑ Nathan A. Berger (July 2015). Murine Models, Energy Balance, and Cancer: 9783319167329: Medicine & Health Science Books @. Springer. ISBN   978-3319167329.
  9. 1 2 Click, Robert E. (2014). "A review: alteration of in vitro reproduction processes by thiols -emphasis on 2-mercaptoethanol". The Journal of Reproduction and Development. 60 (6): 399–405. doi:10.1262/jrd.2014-055. ISSN   1348-4400. PMC   4284312 . PMID   25087867.
  10. ↑ Wilson, DB; Heber-Katz, E; Sprent, J; Howard, JC (1977). "On the possibility of multiple t-cell receptors". Cold Spring Harb Symp Quant Biol. 41 (2): 559–561. doi:10.1101/sqb.1977.041.01.064. PMID   70304.
  11. ↑ Germain, Ronald N. (2015-12-15). "William E. Paul, M.D. (1936-2015), President, The American Association of Immunologists, 1986-1987". Journal of Immunology. 195 (12): 5519–5521. doi: 10.4049/jimmunol.1590025 . ISSN   1550-6606. PMID   26637660. S2CID   12062111.
  12. ↑ Heber-Katz, E; Schwartz, RH; Matis, LA; Fairwell, T; Appella, E; Hansburg, D (1982). "Contribution of antigen-presenting cell major histocompatibility complex gene products to the specificity of antigen-induced T cell activation". J Exp Med. 155 (4): 1086–1099. doi:10.1084/jem.155.4.1086. PMC   2186641 . PMID   6174670.
  13. ↑ Heber-Katz, E.; Hansburg, D.; Schwartz, R. H. (1983). "The Ia molecule of the antigen-presenting cell plays a critical role in immune response gene regulation of T cell activation". The Journal of Molecular and Cellular Immunology: JMCI. 1 (1): 3–18. ISSN   0724-6803. PMID   6101061.
  14. ↑ Heber-Katz, E; Schwartz, RH (1983). The effect of antigen and Ia molecule interaction on immune response gene control, Ir Genes: Past, Present, and Future. Clifton, NJ: Humana Press. p. 295.
  15. ↑ Heber-Katz, Ellen (2015-07-15). "From Immunity and Vaccines to Mammalian Regeneration". The Journal of Infectious Diseases. 212 (Suppl 1): S52–58. doi:10.1093/infdis/jiu637. ISSN   1537-6613. PMC   4574550 . PMID   26116734.
  16. ↑ Heber-Katz, E.; Acha-Orbea, H. (May 1989). "The V-region disease hypothesis: evidence from autoimmune encephalomyelitis". Immunology Today. 10 (5): 164–169. doi:10.1016/0167-5699(89)90174-6. ISSN   0167-5699. PMID   2663017.
  17. ↑ Clark, LD; Clark, RK; Heber-Katz, E (1998). "A new murine model for mammalian wound repair and regeneration". Clinical Immunology and Immunopathology. 88 (1): 33–45. doi:10.1006/clin.1998.4519. PMID   9683548.
  18. ↑ Gourevitch, Dmitri; Kossenkov, Andrew V.; Zhang, Yong; Clark, Lise; Chang, Celia; Showe, Louise C.; Heber-Katz, Ellen (2014-09-01). "Inflammation and Its Correlates in Regenerative Wound Healing: An Alternate Perspective". Advances in Wound Care. 3 (9): 592–603. doi:10.1089/wound.2014.0528. ISSN   2162-1918. PMC   4152783 . PMID   25207202.
  19. ↑ Naviaux, Robert K.; Le, Thuy P.; Bedelbaeva, Khamilia; Leferovich, John; Gourevitch, Dmitri; Sachadyn, Pawel; Zhang, Xiang-Ming; Clark, Lise; Heber-Katz, Ellen (March 2009). "Retained features of embryonic metabolism in the adult MRL mouse". Molecular Genetics and Metabolism. 96 (3): 133–144. doi:10.1016/j.ymgme.2008.11.164. ISSN   1096-7206. PMC   3646557 . PMID   19131261.
  20. 1 2 Zhang, Y; Bedelbaeva, K; Strehin, I; Gourevitch, D; Messersmith, PB; Heber-Katz, E (2015). "Drug-induced Regeneration in Adult Mice". Science Transl Med. 7 (290): 212–221. doi:10.1016/j.msec.2015.04.018. PMID   26042709.
  21. ↑ Heber-Katz, Ellen; Messersmith, Phillip. "Regenerative wound healing via inflammation-modulating biomaterials".{{cite journal}}: Cite journal requires |journal= (help)
  22. ↑ Rai, Muhammad Farooq; Hashimoto, Shingo; Johnson, Eric E.; Janiszak, Kara L.; Fitzgerald, Jamie; Heber-Katz, Ellen; Cheverud, James M.; Sandell, Linda J. (July 2012). "Heritability of articular cartilage regeneration and its association with ear wound healing in mice". Arthritis and Rheumatism. 64 (7): 2300–2310. doi:10.1002/art.34396. ISSN   1529-0131. PMC   3360138 . PMID   22275233.
  23. ↑ Nagai, K; Ideguchi, H; Kajikawa, T; Li, X; Chavakis, T; Cheng, J; Messersmith, PB; Heber-Katz, E; Hajishengallis, G (2020). "An injectable hydrogel-formulated inhibitor of prolyl-4-hydroxylase promotes T regulatory cell recruitment and enhances alveolar bone regeneration during resolution of experimental periodontitis". FASEB Journal. 34 (10): 13726–13740. doi: 10.1096/fj.202001248R . PMC   7722135 . PMID   32812255. S2CID   221180276.
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