100 Matching Annotations
  1. Nov 2019
    1. blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells

      The development of immune checkpoint inhibitor therapies for cancer won James Allison, one of the authors of this paper, and Tasuku Honjo the 2018 Nobel Prize in Physiology or Medicine. Read more at The Guardian.

    2. mice

      There are many regulations on the use of animals in research studies. In 2019, these policies became even more stringent with the passing of the HEARTS Act of 2019. Read more here.

    3. BALB/c

      A laboratory strain of mice useful for studying cancer and immunology.

    4. P. Waterhouse et al., Science 270, 985 (1995)

      Waterhouse et al. investigate the effects of deleting the CTLA-4 from mice. These CTLA-4 deficient mice had disorders of T cell proliferation and quickly died.

    5. J. G. Gribben et al., Proc. Natl. Acad. Sci. U.S.A. 92, 811 (1995)

      Gribben et al. show that CTLA-4 functions to induce cell death of T cells. In biology, many signaling events are also controlled by an off-switch that prevents prolonged or out-of-control signaling. CTLA-4 fulfills this role for T cells.

    6. M. F. Krummel and J. P. Allison, J. Exp. Med. 182, 459 (1995)

      Krummel and Allison study the effect of CTLA-4 engagement. Their anti-CTLA-4 antibody blocks the receptor without engaging it. On its own, blocking the receptor does not have an effect on T-cell responses. Combined with an activation signal, anti-CTLA-4 allows for enhanced proliferation of T cells. The antibodies introduced here are the same ones used in the treatment of mice in this paper.

    7. T. L. Walunas et al., ibid., p. 405

      Walunas et al. show that CTLA-4 is an inhibitor of T cells. Their approach is to cross-link the receptors together, mimicking the cross-linking that would occur naturally upon receptor engagement. The effect of this is inhibition of T cell proliferation.

    8. P. S. Linsley et al., Immunity 1, 793 (1994)

      Linsley et al. study the differences between binding of CD28 and CTLA-4 to B7 molecules. Though they have similar avidities, they bind the B7 surface molecules using different conformations and kinetics.

    9. P. S. Linsley et al., J. Exp. Med. 174, 561 (1991)

      Linsley et al. show that CTLA-4, like CD28, binds B7. Using a soluble version of CTLA-4, they show that it binds to B7 with an affinity of 12 nM.

    10. K. Harper et al., J. Immunol. 147, 1037 (1991)

      Harper et al. present compelling evidence that CTLA-4 and CD28 share a similar function. They found that the receptors share similarities in structure, sequence, gene location, and expression patterns.

    11. J. F. Brunet et al., Nature 328, 267 (1987)

      Brunet et al. identify the sequence of the CTLA-4 receptor. They note that it is part of the immunoglobulin and has hydrophobic flanking sequences reminiscent of a membrane-bound protein. They also show that its expression is restricted to activated lymphocytes (T cells and B cells).

    12. P. S. Linsley, J. Exp. Med. 182, 289 (1995)

      In this commentary, Linsley speculates on how the evidence for the roles of CD28 and CTLA-4 fits together. T-cell activation is more complex than scientists originally thought.

    13. J. A. Bluestone, ibid. 2, 555 (1995)

      In this minireview, Bluestone summarizes the studies showing the nuances of CD28-mediated signaling. He discusses that different B7 molecules result in differing levels of activation, and that CTLA-4 has an inhibitory effect.

    14. M. K. Jenkins, Immunity 1, 443 (1994)

      In this minireview, Jenkins summarizes the evidence for the role of CTLA-4. It was shown from multiple studies that CTLA-4 has an immunosuppressive effect.

    15. S. Baskar et al., Proc. Natl. Acad. Sci. U.S.A. 90, 5687 (1993)

      Baskar et al. investigate the effect of B7 expression in tumor cells on the helper T cell immune response. They show that engineered tumor cells generate a helper T cell response and tumor rejection.

    16. S. E. Townsend and J. P. Allison, Science 259, 368 (1993)

      Townsend and Allison investigate whether expressing B7 on the surface of a tumor will enhance its rejection. They show that B7 expression results in a cytotoxic T cell immune response.

    17. L. Chen, S. Ashe, W. A. Brady, l. Hellstrom, K. E. Hellstrom et al., Cell 71, 1093 (1992)

      Chen et al. investigate whether expressing B7 on the surface of a tumor will enhance its rejection. They show a B7-dependent immune response by cytotoxic T cells.

    18. C. H. June, J. A. Bluestone, L. M. Nadler, C. B. Thompson, Immunol. Today 15, 321 (1994)

      June, Bluestone, Nadler, and Thompson review the research on B7 and CD28. Though they are the most commonly found members, each of these molecules is part of a larger receptor family of related molecules.

    19. P. S. Linsley and J. A. Ledbetter

      Linsley and Ledbetter summarize the research on CD28 and B7 molecules. The costimulatory signal needed for full T-cell activation is supplied through these surface molecules.

    20. D. L. Mueller, M. K. Jenkins, R. H. Schwartz, Ann. Rev. Immunol. 7, 445 (1989)

      Mueller, Jenkins, and Schwartz review the body of research on T cell costimulatory signalling pathways. In the few years after the discovery of the T-cell receptor, which directly binds the antigen to which a T cell is responding, researchers proposed that other signals are needed for T cells to become fully activated. This led to the two-signal model of T-cell activation described in this review.

    21. ibid.

      The latin word ibidem means in the same place. To save space, some authors use ibid. to refer to a reference from the same journal as the previous one.

    22. with μg

      Should say 100 ug.

    23. 18

      Needs to be italic

    24. antigen transfer

      The process by which antigen-presenting cells uptake antigenic molecules from their surroundings, so that they may display them on their surface.

    25. antigen presentation

      The process of exposing T cells to molecular signatures of disease through displaying them on the surface of antigen-presenting cells.

    26. ex vivo

      Outside of the living organism. In ex vivo experiments, cells originate in an organism, are extracted and modified, and then can be reintroduced.

    27. pulsing dendritic cells with antigen

      The final tumor-specific method of generating immunity is to directly produce dendritic cells (the most common type of antigen-presenting cells) which display tumor antigens.

    28. produce granulocyte-macrophage colony-simulating factor

      Another tumor-specific method of generating immunity is to modify tumor cells so that they produce a molecule which encourages the immune system's professional antigen-presenting cells (APCs) to take up molecules from the tumor cells. This means that APCs are better able to "train" T cells to recognize the signatures of the tumor.

    29. engineering tumor cells to express MHC class II molecules

      Another tumor-specific method is modifying tumor cells so they become more similar to antigen-presenting cells. This allows T cells to recognize them more easily.

    30. induction of B7 expression, rely on enhancing the costimulatory activity of the tumor cells themselves

      One such tumor-specific method of generating an immune response is to modify tumor cells so that they produce costimulatory molecules that enhance activation of T cells they come in contact with.

    31. Current methods of enhancing antitumor immunity generally require the engineering of tumor cells

      There are other methods of generating an immune response against cancer. Unlike this one, they are specific to the type of tumor, and require that the tumor cells be obtained and engineered in some way to become more visible to the immune system.

    32. we have observed these effects against unmanipulated, wild-type tumors

      Anti-CTLA-4 treatment can be used for the normal tumors that a patient's immune system may get exposed to. It is not necessary to first extract tumor cells and modify them for the immune system to be able to recognize them. This makes it a very powerful treatment.

    33. CTLA-4 blockade might sustain proliferation of activated T cells by removing inhibitory signals that would normally terminate the response

      Another proposed mechanism of the effectiveness of CTLA-4 blockade is given. This mechanism could work in tandem with the previous one. Anti-CTLA-4 treatment may be allowing activated T cells to divide and grow for a longer period of time, so that there is a larger number of them circulating in the body and available to respond to the cancerous cells.

    34. removal of inhibitory signals may lower the overall threshold of T cell activation and allow normally unreactive T cells to become activated

      The authors propose that the effectiveness of CTLA-4 blockade may arise from lowering the number or concentration of antigens that T cells expect to be exposed to before they become fully activated. That is, anti-CTLA-4 may be allowing T cells to become more sensitive.

    35. antigens are most likely transferred to and presented by host

      For the immune system to be able to respond to molecules on the surface of cancerous cells, these molecules are first presented on the surface of specialized immune cells. Through this antigen-presentation process, T cells able to respond to these molecules are activated and expanded.

    36. APCs

      Antigen presenting cells. Specialized immune cells which allow T cells to be exposed to the antigens present in the body. This allows T cells to become activated so they can target those pathogens or diseased cells.

    37. in vivo

      Within a living organism (as opposed to in vitro, or in cells grown in the lab)

    38. it has been shown that anti-CTLA-4 interferes with signals that normally down-regulate T cell responses

      Administering anti-CTLA-4 treatment in the absence of a tumor causes T cell responses to slow down. At the time of publishing of this paper, it was not clear why this was the case.

    39. removing inhibitory signals in the costimulatory pathway can enhance antitumor immunity

      The 2019 Nobel Prize in Physiology or Medicine was awarded jointly to James Allison and Tasuku Honjo for their work on antitumor immunity. Jim Allison is one of the authors on this seminal paper, where the significant discoveries on the role of CTLA-4 were beginning to be made. Both James Allison and Tasuku Honjo showed that blocking inhibitory signals received by T cells can greatly enhance antitumor immunity. As you read in this paper, Jim Allison showed that blocking CTLA-4 achieves this effect; Tasuku Honjo was honored for similar work on another inhibitory molecule, PD-1. See the Nobel Prize announcement and an interview by a member of the Nobel committee here, and listen to various interviews with James Allison here.

    40. rapidly growing tumors, whereas 7 of 10 mice treated with anti-CTLA-4 were tumor-free by day 25 after injection

      Similar trends were observed in this experiment. Mice left untreated grew tumors rapidly, while the majority of those treated with anti-CTLA-4 remained tumor-free.

    41. injected with 4×1054×105<math xmlns="http://www.w3.org/1998/Math/MathML"><mn>4</mn><mo>×</mo><msup><mn>10</mn><mn>5</mn></msup></math> Sa1N tumor cells

      The experiment was repeated with a much larger number of tumor cells injected. This is to ensure that the effects seen rely only on the treatment course and not on other factors.

    42. only two mice treated with anti-CTLA-4 had tumors by day 30, and one additional mouse developed a tumor around day 40

      By treating the mice with anti-CTLA-4, the authors were able to prevent tumor growth in two mice, and delay it considerably in the other three.

    43. measurable, rapidly growing tumors within 7 days

      Those mice that were not treated grew tumors in the first week of the experiment.

    44. All control mice injected subcutaneously with 1×1061×106<math xmlns="http://www.w3.org/1998/Math/MathML"><mn>1</mn><mo>×</mo><msup><mn>10</mn><mn>6</mn></msup></math> Sa1N cells

      The authors injected groups of 5 mice each with SA1N cells causing fibrocarcinoma.

  2. Oct 2019
    1. A/JCr mice

      Another laboratory strain of mice useful for studying cancer and immunology.

    2. delaying treatment appeared to be more effective

      Not only was delaying treatment effective, it was more effective than treating the mice on the same day that tumors are introduced.

    3. we injected groups of mice with 2×1062×106<math xmlns="http://www.w3.org/1998/Math/MathML"><mn>2</mn><mo>×</mo><msup><mn>10</mn><mn>6</mn></msup></math> wild-type 51BLim10 tumor cells and treated them with anti-CTLA-4 beginning on day 0 as before, or beginning 7 days later

      The authors conduct a new set of experiments to check whether administering anti-CTLA-4 after tumors are detected is as effective as administering it at the same time tumors are introduced. If they are able to successfully treat mice after tumors are already established, then maybe this treatment could work for human patients as well!

    4. wild-type

      Unmodified; that is, wild-type 51BLim10 cells do not have the extra genes which introduce B7 or the extra modifications which silence it.

    5. These results demonstrate that tumor rejection mediated by CTLA-4 blockade results in immunologic memory

      The mice described in this section rejected the tumors twice: the first time, they were being treated with anti-CTLA-4, and the second time, they were not. This means that their immune system was able to fight off the second tumor on its own, and much faster than mice which had not previously survived exposure to the tumor. These are hallmarks of immunologic memory, the same phenomenon that ensures you only get chicken pox once in your life!

    6. Only one of the previously immunized mice had a detectable tumor by day 14

      Most of the previously immunized mice did not develop tumors of detectable size; that is, their immune system was able to kill all the tumor cells almost as soon as they were introduced. Only one of the mice developed a detectable tumor, but the growth was very slow.

    7. control animals had progressively growing tumors by 14 days after injection, developed massive tumor burdens, and required euthanasia by day 35

      If mice were not previously exposed to the tumor cells along with a treatment, they did not fare very well.

    8. significant protection against a secondary challenge

      The mice which previously mounted an immune response with the help of anti-CTLA-4 were able to leverage a similar response toward this re-exposure. Remember that naive mice exposed to half this many tumor cells were not able to control the cancer's growth.

    9. Mice that had rejected V51BLim10 tumor cells as a result of treatment with anti-CTLA-4 were challenged with 4×1064×106<math xmlns="http://www.w3.org/1998/Math/MathML"><mn>4</mn><mo>×</mo><msup><mn>10</mn><mn>6</mn></msup></math> wild-type 51BLim10 cells 70 days after their initial tumor injections

      The authors injected the mice which were previously treated with unmodified tumor. If they developed an immune memory, they may be able to clear this tumor even though it is not expressing B7 and they have not been given anti-CTLA4 antibodies!

    10. secondary challenge

      A second exposure to the same threat. The immune system is under certain conditions able to remember threats it has encountered before and react to them more quickly and effectively upon each subsequent exposure.

    11. Anti-CTLA-4 appeared to be less effective at a tumor dose of 1×1061×106<math xmlns="http://www.w3.org/1998/Math/MathML"><mn>1</mn><mo>×</mo><msup><mn>10</mn><mn>6</mn></msup></math> cells, where treatment resulted in significantly reduced tumor growth rates, but four of five mice developed progressively growing tumors

      The authors repeated the experiment with an even lower tumor burden of 1x10\(^6\) cells, and found that the effectiveness of treatment was reduced at this dose. They do not propose a reason for this. Perhaps you can think of one!

    12. Anti-CTLA-4 treatment had a dramatic effect on tumor growth

      The treated mice had much better outcomes than the untreated mice, which were euthanized after 35 days.

    13. injected with 2×1062×106<math xmlns="http://www.w3.org/1998/Math/MathML"><mn>2</mn><mo>×</mo><msup><mn>10</mn><mn>6</mn></msup></math> tumor cells

      The authors decided to check if there is an effect to changing the tumor dose. They halved the dose to 2x10\(^6\) and had a group of untreated and a group of anti-CTLA-4 treated mice.

    14. the growth of V51BLim10, a vector control tumor cell line that does not express B7

      This set of experiments was conducted with a variant of the same murine colon cancer tumor cells, but this time the tumors do not express B7. Thus the tumors are not able to provide the secondary signal to T cells.

    15. completely rejected their tumors after a short period of limited growth

      The mice treated with antibodies against CTLA-4 completely recovered and were able to clear the tumors.

    16. treated with anti-CTLA-4

      A third group of mice received anti-CTLA-4 antibodies as treatment.

    17. developed progressively growing tumors and required euthanasia by 35 days after inoculation

      The mice which received these treatments could not control the growth of their tumors. They died 35 days after the tumors were injected.

    18. injected with 4×1064×106<math xmlns="http://www.w3.org/1998/Math/MathML"><mn>4</mn><mo>×</mo><msup><mn>10</mn><mn>6</mn></msup></math> V51BLim10 tumor cells and left untreated, or treated with anti-CD28

      The mice were split into groups that received different treatment regimens. Two of the groups were untreated, or were treated only with anti-CD28 antibodies.

    19. three of five mice treated with anti-CTLA-4 developed very small tumors, all of which regressed completely by day 17

      The third group of mice was treated with antibodies targeting CTLA-4. Those mice were able to clear the tumors faster, by day 17, if they developed tumors at all.

    20. All mice in the untreated and antiCD28-treated groups developed small tumors that grew progressively for 5 to 10 days and then ultimately regressed in 8 of the 10 mice by about day 23 after injection. The two small tumors that did not regress remained static for more than 90 days

      Two groups were injected with anti-CD28 or not treated. Most of the mice in these two groups cleared the tumors, but did so by day 23. Two of the mice did not completely clear the tumors but were able to keep them from growing further.

    21. Two groups were treated with a series of intraperitoneal injections of either anti-CTLA-4 or anti-CD28

      The authors injected groups of mice with tumor cells expressing B7-1 molecules. These mice were then treated with two different regimens. One group of mice was injected with antibodies targeting CTLA-4, and another with antibodies targeting CD28.

    22. untreated controls

      The authors had a control group of mice which were injected with tumor cells expressing B7-1 molecules, but were not treated with any antibodies.

    23. B7-1 expression was partially successful at inducing rejection

      If cancerous cells express B7-1, the immune system is better able to respond to them and clear the tumor.

    24. murine

      Relating to or originating from mice.

    25. bivalent antibody

      An antibody able to bind two of its targets at once.

    26. model systems

      Scientists often use models to represent complex systems.

    27. raise the possibility that blockade of inhibitory signals delivered by CTLA-4-B7 interactions might augment T cell responses to tumor cells and enhance antitumor immunity

      The pieces of evidence outlined in this paragraph led the authors to conclude that blocking tumors from being able to engage CTLA-4 might result in T cells being better able to fight off tumors.

    28. mice deficient in CTLA-4 exhibit severe T cell proliferative disorders

      The absence of CTLA-4 results in out-of-control cell division of T cells. Even though CTLA-4 is an inhibitory receptor, it is needed to produce the right balance of T cell activation and its complete absence can be dangerous to organisms.

    29. CTLA-4 engagement can induce apoptosis in activated T cells

      Another effect of CTLA-4 signaling is the programmed cell death of T cells. This is another way for CTLA-4 to dampen T cell responses.

    30. greatly augment T cell responses to nominal peptide antigen or the superantigen Staphylococcus enterotoxin B in vivo

      Blocking CTLA-4 also increases T cell activation that happens as a result of encountering foreign invaders.

    31. enhances proliferative responses

      The inhibitory CTLA-4 receptor can be blocked by using soluble antibody. Blocking the effects of CTLA-4 allows T cells to activate and proliferate normally upon induction by anti-CD3.

    32. Fab fragments

      The antigen-binding fragment of antibody, i.e the domain which binds specifically to the target of the antibody.

    33. induced by antibody to CD3 (anti-CD3)

      CD3 is a co-receptor alongside the T-cell receptor. Together, they provide the primary signal of T cell activation. In this experiment, the scientists tried to add anti-CD3 antibody, which would normally result in T cell activation. However, the inhibitory effect of CTLA-4 wins out over this activation technique.

    34. antibody cross-linking of CTLA-4 has been shown to inhibit

      Using antibodies, scientists can induce dimerization of the receptor CTLA-4. Dimerization is often the cause of signaling through a receptor. This experiment shows that the effect of the CTLA-4 signaling is inhibition of T cell activation and expansion.

    35. proliferation and interleukin-2 production

      Two indicators of T cell activation. Once activated, T cells divide rapidly and produce a molecule called interleukin-2.

    36. In vitro

      "In the glass," that is, experiments done in test tubes, not in organisms.

    37. binds both B7-1 and B7-2 with affinities much greater than does CD28

      CTLA-4 competes with CD28 for binding to the B7 family of molecules.

    38. homolog

      A related protein, usually with very similar sequence and structure.

    39. costimulation is more complex than originally thought and involves competing stimulatory and inhibitory signaling events

      The overall activation of T cells is also influenced by another type of secondary signal. In addition to stimulatory signals discussed above, T cells may also encounter inhibitory signals. The balance of these two signaling events results in the overall level of activation.

    40. 3,

      This needs to be italic since it is a reference.

    41. tumor cells expressing costimulatory B7 molecules induced potent responses against both modified and unmodified tumor cells

      Introducing the genes for B7 molecules into tumor cells allows them to provide the secondary signal needed to activate T cells. This allows the immune system to respond to those modified tumor cells, as well as any future tumors of the same type that they encounter (even if the latter do not express B7).

    42. transfected

      A technique by which the genes in a cell are modified.

    43. appears to be provided by the interaction of CD28 on T cells with its primary ligands B7-1 (CD80) and B7-2 (CD86) on the surface of specialized antigen-presenting cells (APCs)

      The two-signal model of T-cell activation was confirmed when scientists found that specialized immune cells, called antigen-presenting cells, provide a secondary signal to T cells in order to activate them. This secondary signal comes from the interaction of the B7 family of molecules (on the surface of APCs) with the CD28 receptor (on the surface of T cells).

    44. additional costimulatory signals are necessary for T cell activation

      Mueller, Jenkins and Schwartz summarize the models proposed by several scientists to explain why T cells only respond to foreign invaders, and not to peptide-MHC on healthy cells. They summarize it as the "two-signal model of T-cell activation": there must be another signal necessary for T cells to be activated.

    45. B7 family of costimulatory molecules

      A family of binders to CD28. The two most important members are B7-1 and B7-2, mentioned below.

    46. antigenic peptide bound to major histocompatibility complex (MHC)

      The target for T cell receptors is always a short peptide displayed on the surface of the cells. The protein responsible for displaying the peptides is called the major histocompatibility complex.

    47. T cell receptor

      The receptor used by T cells to recognize specific antigens.

    48. antigens

      Molecules recognized by the immune system; signatures of disease.

    49. resulted in immunity to a secondary exposure to tumor cells

      Administering antibodies against CTLA-4 also allows the mice to prevent establishment of tumors due to future exposure.

    50. resulted in the rejection of tumors, including preestablished tumors

      By preventing CTLA-4 from binding to its ligands, T cells can now be activated more potently. This allows them to kill cancer cells.

    51. in vivo administration of antibodies to CTLA-4

      The authors injected mice with antibodies that bind CTLA-4.

    52. CTLA-4

      Another receptor on the surface of T cells, with an opposite effect compared to CD28. Binding to CTLA-4 causes damping of T cell activation.

    53. T cells

      White blood cells central to adaptive immunity. T cells are able to recognize if cells are diseased and can kill them so they don't spread throughout the body.

    54. CD28-mediated costimulation

      To become fully activated, T cells need to receive a signal through the CD28 receptor on their surface.

    55. immunogenicity

      The ability of the immune system to recognize diseased or foreign cells.

    56. providing tumor lines

      Science is collaborative.