Programmed cell death protein 1 explained

Programmed cell death protein 1 (PD-1), (CD279 cluster of differentiation 279). PD-1 is a protein encoded in humans by the PDCD1 gene.[1] [2] PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.[3]

PD-1 is an immune checkpoint and guards against autoimmunity through two mechanisms. First, it promotes apoptosis (programmed cell death) of antigen-specific T-cells in lymph nodes. Second, it reduces apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells).[4] [5]

PD-1 inhibitors, a new class of drugs that block PD-1, activate the immune system to attack tumors and are used to treat certain types of cancer.[3] [6]

PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells. PD-1 binds two ligands, PD-L1 and PD-L2.

Discovery

In a screen for genes involved in apoptosis, Yasumasa Ishida, Tasuku Honjo and colleagues at Kyoto University in 1992 discovered and named PD-1.[7] [8] In 1999, the same group demonstrated that mice where PD-1 was knocked down were prone to autoimmune disease and hence concluded that PD-1 was a negative regulator of immune responses.

Structure

PD-1 is a type I membrane protein of 288 amino acids. PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators.[7] The protein's structure includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail. The intracellular tail contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates T-cell receptor TCR signals.[7] [9] This is consistent with binding of SHP-1 and SHP-2 phosphatases to the cytoplasmic tail of PD-1 upon ligand binding. In addition, PD-1 ligation up-regulates E3-ubiquitin ligases CBL-b and c-CBL that trigger T cell receptor down-modulation.[10] PD-1 is expressed on the surface of activated T cells, B cells, and macrophages,[11] suggesting that compared to CTLA-4, PD-1 more broadly negatively regulates immune responses.

Ligands

PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family.[12] [13] PD-L1 protein is upregulated on macrophages and dendritic cells (DC) in response to LPS and GM-CSF treatment, and on T cells and B cells upon TCR and B cell receptor signaling, whereas in resting mice, PD-L1 mRNA can be detected in the heart, lung, thymus, spleen, and kidney.[14] PD-L1 is expressed on almost all murine tumor cell lines, including PA1 myeloma, P815 mastocytoma, and B16 melanoma upon treatment with IFN-γ.[15] [16] PD-L2 expression is more restricted and is expressed mainly by DCs and a few tumor lines.[13]

Function

Several lines of evidence suggest that PD-1 and its ligands negatively regulate immune responses. PD-1 knockout mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy on the C57BL/6 and BALB/c backgrounds, respectively.[17] [18] In vitro, treatment of anti-CD3 stimulated T cells with PD-L1-Ig results in reduced T cell proliferation and IFN-γ secretion.[12] IFN-γ is a key pro-inflammatory cytokine that promotes T cell inflammatory activity. Reduced T cell proliferation was also correlated with attenuated IL-2 secretion and together, these data suggest that PD-1 negatively regulates T cell responses.[19]

Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg) CD4+ and CD8+ T cells suggest that CD8+ T cells are more susceptible to inhibition by PD-L1, although this could be dependent on the strength of TCR signaling. Consistent with a role in negatively regulating CD8+ T cell responses, using an LCMV viral vector model of chronic infection, Rafi Ahmed's group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus specific CD8+ T cells, which can be reversed by blocking the PD-1-PD-L1 interaction.[20]

Expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells.[15] [16] Expression of PD-L1 on tumors is correlated with reduced survival in esophageal, pancreatic and other types of cancers, highlighting this pathway as a target for immunotherapy.[3] [21] Triggering PD-1, expressed on monocytes and up-regulated upon monocytes activation, by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.[22]

In mice, expression of this gene is induced in the thymus when anti-CD3 antibodies are injected and large numbers of thymocytes undergo apoptosis. Mice deficient for this gene bred on a BALB/c background developed dilated cardiomyopathy and died from congestive heart failure. These studies suggest that this gene product may also be important in T cell function and contribute to the prevention of autoimmune diseases.[2]

Overexpression of PD1 on CD8+ T cells is one of the indicators of T-cell exhaustion (e.g. in chronic infection or cancer).[3] [23]

Clinical significance

Cancer

PD-L1, the ligand for PD1, is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established.[24] [25] [3] Monoclonal antibodies targeting PD-1 that boost the immune system are being developed for the treatment of cancer.[26] Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumor activity. This is known as immune checkpoint blockade.

Combination therapy using both anti-PD1 along with anti-CTLA4 therapeutics have emerged as important tumor treatments within the field of checkpoint inhibition.

A combination of PD1 and CTLA4 antibodies has been shown to be more effective than either antibody alone in the treatment of a variety of cancers. The effects of the two antibodies do not appear to be redundant.[27] [28] [29] Anti-CTLA4 treatment leads to an enhanced antigen specific T cell dependent immune reaction while anti-PD-1 appears to reactivate CD8+ T cells ability to lyse cancer cells.[30] [31]

In clinical trials, combination therapy has been shown to be effective in reducing tumor size in patients that are unresponsive to single co-inhibitory blockade, despite increasing levels of toxicity due to anti-CTLA4 treatment.[32] A combination of PD1 and CTLA4 induced up to a ten-fold higher number of CD8+ T cells that are actively infiltrating the tumor tissue.[30] The authors hypothesized that the higher levels of CD8+ T cell infiltration was due to anti-CTLA-4 inhibited the conversion of CD4 T cells to T regulator cells and further reduced T regulatory suppression with anti-PD-1. This combination promoted a more robust inflammatory response to the tumor that reduced the size of the cancer. Most recently, the FDA has approved a combination therapy with both anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab) in October 2015.[33]

The molecular factors and receptors necessary making a tumor receptive to anti-PD1 treatment remains unknown. PD-L1 expression on the surface on cancer cells plays a significant role. PD-L1 positive tumors were twice as likely to respond to combination treatment.[32] However patients with PD-L1 negative tumors also have limited response to anti-PD1, demonstrating that PD-L1 expression is not an absolute determinant of the effectiveness of therapy.

Higher mutational burden in the tumor is correlated with a greater effect of the anti-PD-1 treatment. In clinical trials, patients who benefited from anti-PD1 treatment had cancers, such as melanoma, bladder cancer, and gastric cancer, that had a median higher average number of mutations than the patients who did not respond to the therapy. However, the correlation between higher tumor burden and the clinical effectiveness of PD-1 immune blockade is still uncertain.

The 2018 Nobel Prize for Medicine was awarded to James P Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation".

Anti-PD-1 therapeutics

See main article: PD-1 and PD-L1 inhibitors. A number of cancer immunotherapy agents that target the PD-1 receptor have been developed.

One such anti-PD-1 antibody drug, nivolumab, (Opdivo - Bristol Myers Squibb), produced complete or partial responses in non-small-cell lung cancer, melanoma, and renal-cell cancer, in a clinical trial with a total of 296 patients.[34] Colon and pancreatic cancer did not have a response. Nivolumab (Opdivo, Bristol-Myers Squibb) was approved in Japan in July 2014 and by the US FDA in December 2014 to treat metastatic melanoma.

Pembrolizumab (Keytruda, MK-3475, Merck), which also targets PD-1 receptors, was approved by the FDA in Sept 2014 to treat metastatic melanoma. Pembrolizumab has been made accessible to advanced melanoma patients in the UK via UK Early Access to Medicines Scheme (EAMS) in March 2015. It is being used in clinical trials in the US for lung cancer, lymphoma, and mesothelioma. It has had measured success, with little side effects. It is up to the manufacturer of the drug to submit application to the FDA for approval for use in these diseases. On October 2, 2015, Pembrolizumab was approved by FDA for advanced (metastatic) non-small cell lung cancer (NSCLC) patients whose disease has progressed after other treatments.[35]

Toripalimab is a humanized IgG4 monoclonal antibody against PD-1 which was approved in China in 2018 and in the United States in 2023.[36] [37] [38]

Drugs in early stage development targeting PD-1 receptors (checkpoint inhibitors) include pidilizumab (CT-011, Cure Tech) and BMS-936559 (Bristol Myers Squibb). Both atezolizumab (MPDL3280A, Roche) and avelumab (Merck KGaA, Darmstadt, Germany and Pfizer) target the similar PD-L1 receptor.

Animal studies

HIV

Drugs targeting PD-1 in combination with other negative immune checkpoint receptors, such as (TIGIT), may augment immune responses and/or facilitate HIV eradication.[39] [40] T lymphocytes exhibit elevated expression of PD-1 in cases of chronic HIV infection.[41] Heightened presence of the PD-1 receptors corresponds to exhaustion of the HIV specific CD8+ cytotoxic and CD4+ helper T cell populations that are vital in combating the virus. Immune blockade of PD-1 resulted in restoration of T cell inflammatory phenotype necessary to combat the progression of disease.[41]

Alzheimer's disease

Blocking of PD-1 leads to a reduction in cerebral amyloid-β plaques and improves cognitive performance in mice.[42] Immune blockade of PD-1 evoked an IFN-γ dependent immune response that recruited monocyte-derived macrophages to the brain that were then capable of clearing the amyloid-β plaques from the tissue. Repeated administrations with anti-PD-1 were found to be necessary to maintain the therapeutic effects of the treatment. Amyloid fibrils are immunosuppressive and this finding has been separately confirmed by examining the effects of the fibrils in neuroinflammatory diseases.[43] [44] [45] PD-1 counteracts the effects of the fibrils by boosting immune activity and triggering an immune pathway that allows for brain repair.[42]

Further reading

External links

Notes and References

  1. Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T . Structure and chromosomal localization of the human PD-1 gene (PDCD1) . Genomics . 23 . 3 . 704–6 . October 1994 . 7851902 . 10.1006/geno.1994.1562 .
  2. Web site: Entrez Gene: PDCD1 programmed cell death 1.
  3. Syn NL, Teng MW, Mok TS, Soo RA . De-novo and acquired resistance to immune checkpoint targeting . The Lancet. Oncology . 18 . 12 . e731-e741 . December 2017 . 29208439 . 10.1016/s1470-2045(17)30607-1 .
  4. Francisco LM, Sage PT, Sharpe AH . The PD-1 pathway in tolerance and autoimmunity . Immunological Reviews . 236 . 219–42 . July 2010 . 20636820 . 2919275 . 10.1111/j.1600-065X.2010.00923.x .
  5. Fife BT, Pauken KE . The role of the PD-1 pathway in autoimmunity and peripheral tolerance . Annals of the New York Academy of Sciences . 1217 . 45–59 . January 2011 . 1 . 21276005 . 10.1111/j.1749-6632.2010.05919.x . 2011NYASA1217...45F . 23843848 .
  6. News: New Bristol-Myers Drug Helped Skin-Cancer Patients in Trial Live Longer. Loftus P . Wall Street Journal . 16 Nov 2014. 24 Nov 2014.
  7. Ishida Y, Agata Y, Shibahara K, Honjo T . Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death . The EMBO Journal . 11 . 11 . 3887–95 . November 1992 . 1396582 . 556898 . 10.1002/j.1460-2075.1992.tb05481.x.
  8. Bardhan K, Anagnostou T, Boussiotis VA . The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation . Frontiers in Immunology . 7 . 550 . 2016 . 28018338 . 5149523 . 10.3389/fimmu.2016.00550 . free .
  9. Blank C, Mackensen A . Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion . Cancer Immunology, Immunotherapy . 56 . 5 . 739–45 . May 2007 . 17195077 . 10.1007/s00262-006-0272-1 . 11384162 . 11030209 .
  10. Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D . PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells . EMBO Molecular Medicine . 3 . 10 . 581–92 . October 2011 . 21739608 . 3191120 . 10.1002/emmm.201100165 .
  11. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T . Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes . . 8 . 5 . 765–72 . May 1996 . 8671665 . 10.1093/intimm/8.5.765 .
  12. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T . Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation . The Journal of Experimental Medicine . 192 . 7 . 1027–34 . October 2000 . 11015443 . 2193311 . 10.1084/jem.192.7.1027 .
  13. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ . PD-L2 is a second ligand for PD-1 and inhibits T cell activation . Nature Immunology . 2 . 3 . 261–8 . March 2001 . 11224527 . 10.1038/85330 . 27659586 .
  14. Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, Azuma M, Yagita H . Expression of programmed death 1 ligands by murine T cells and APC . Journal of Immunology . 169 . 10 . 5538–45 . November 2002 . 12421930 . 10.4049/jimmunol.169.10.5538 . free .
  15. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N . Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade . Proceedings of the National Academy of Sciences of the United States of America . 99 . 19 . 12293–7 . September 2002 . 12218188 . 129438 . 10.1073/pnas.192461099 . 2002PNAS...9912293I . free .
  16. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF . PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells . Cancer Research . 64 . 3 . 1140–5 . February 2004 . 14871849 . 10.1158/0008-5472.CAN-03-3259 . free .
  17. Nishimura H, Nose M, Hiai H, Minato N, Honjo T . Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor . Immunity . 11 . 2 . 141–51 . August 1999 . 10485649 . 10.1016/S1074-7613(00)80089-8 . free .
  18. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T . Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice . Science . 291 . 5502 . 319–22 . January 2001 . 11209085 . 10.1126/science.291.5502.319 . 2001Sci...291..319N .
  19. Carter L, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, Collins M, Honjo T, Freeman GJ, Carreno BM . PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2 . European Journal of Immunology . 32 . 3 . 634–43 . March 2002 . 11857337 . 10.1002/1521-4141(200203)32:3<634::AID-IMMU634>3.0.CO;2-9 . free .
  20. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R . Restoring function in exhausted CD8 T cells during chronic viral infection . Nature . 439 . 7077 . 682–7 . February 2006 . 16382236 . 10.1038/nature04444 . 2006Natur.439..682B . 205210800 .
  21. Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, Mizuno T, Yoriki R, Kashizuka H, Yane K, Tsushima F, Otsuki N, Yagita H, Azuma M, Nakajima Y . Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer . Clinical Cancer Research . 11 . 8 . 2947–53 . April 2005 . 15837746 . 10.1158/1078-0432.CCR-04-1469 . free .
  22. Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy JP, Douek DC, Haddad EK, Sekaly RP . Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection . Nature Medicine . 16 . 4 . 452–9 . April 2010 . 20208540 . 4229134 . 10.1038/nm.2106 .
  23. Pauken KE, Wherry EJ . Overcoming T cell exhaustion in infection and cancer . Trends in Immunology . 36 . 4 . 265–76 . 2015 . 25797516 . 4393798 . 10.1016/j.it.2015.02.008 .
  24. Wang X, Teng F, Kong L, Yu J . PD-L1 expression in human cancers and its association with clinical outcomes . OncoTargets and Therapy . 9 . 5023–39 . August 2016 . 27574444 . 4990391 . 10.2147/OTT.S105862 . free .
  25. Gandini S, Massi D, Mandalà M . PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis . Critical Reviews in Oncology/Hematology . 100 . 88–98 . April 2016 . 26895815 . 10.1016/j.critrevonc.2016.02.001 .
  26. Weber J . Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical background: CTLA-4 and PD-1 blockade . Seminars in Oncology . 37 . 5 . 430–9 . October 2010 . 21074057 . 10.1053/j.seminoncol.2010.09.005 .
  27. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS . Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients . Nature . 515 . 7528 . 563–7 . November 2014 . 25428504 . 4836193 . 10.1038/nature14011 . 2014Natur.515..563H .
  28. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA . Genetic basis for clinical response to CTLA-4 blockade in melanoma . EN . The New England Journal of Medicine . 371 . 23 . 2189–99 . December 2014 . 25409260 . 10.1056/nejmoa1406498 . 4315319.
  29. Buchbinder EI, Desai A . CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition . American Journal of Clinical Oncology . 39 . 1 . 98–106 . February 2016 . 26558876 . 4892769 . 10.1097/COC.0000000000000239 .
  30. Curran MA, Montalvo W, Yagita H, Allison JP . PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors . en . Proceedings of the National Academy of Sciences of the United States of America . 107 . 9 . 4275–80 . March 2010 . 20160101 . 2840093 . 10.1073/pnas.0915174107 . 2010PNAS..107.4275C . free .
  31. Sliwkowski MX, Mellman I . Antibody therapeutics in cancer . en . Science . 341 . 6151 . 1192–8 . September 2013 . 24031011 . 10.1126/science.1241145 . 2013Sci...341.1192S . 29830409 .
  32. Chen DS, Mellman I . Oncology meets immunology: the cancer-immunity cycle . Immunity . 39 . 1 . 1–10 . July 2013 . 23890059 . 10.1016/j.immuni.2013.07.012 . free .
  33. Topalian SL, Taube JM, Anders RA, Pardoll DM . Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy . Nature Reviews. Cancer . 16 . 5 . 275–87 . May 2016 . 27079802 . 10.1038/nrc.2016.36 . 5381938.
  34. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M . Safety, activity, and immune correlates of anti-PD-1 antibody in cancer . The New England Journal of Medicine . 366 . 26 . 2443–54 . June 2012 . 22658127 . 3544539 . 10.1056/NEJMoa1200690.
  35. FDA approves Keytruda for advanced non-small cell lung cancer . U.S. Food and Drug Administration (FDA) Press Release . 2 October 2015 .
  36. Web site: Toripalimab - Shanghai Junshi Biosciences - AdisInsight. adisinsight.springer.com. 2019-08-25.
  37. Keam, S.J. . Toripalimab: First Global Approval . Drugs . 79 . 573–578 . 2019 . 5 . 10.1007/s40265-019-01076-2 . 30805896 . free .
  38. Web site: FDA approves toripalimab-tpzi for nasopharyngeal carcinoma . US Food and Drug Administration . October 27, 2023.
  39. Porichis F, Kaufmann DE . Role of PD-1 in HIV pathogenesis and as target for therapy . Current HIV/AIDS Reports . 9 . 1 . 81–90 . March 2012 . 22198819 . 3731769 . 10.1007/s11904-011-0106-4 .
  40. Chew GM, Fujita T, Webb GM, Burwitz BJ, Wu HL, Reed JS, Hammond KB, Clayton KL, Ishii N, Abdel-Mohsen M, Liegler T, Mitchell BI, Hecht FM, Ostrowski M, Shikuma CM, Hansen SG, Maurer M, Korman AJ, Deeks SG, Sacha JB, Ndhlovu LC . TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection . PLOS Pathogens . 12 . 1 . e1005349 . January 2016 . 26741490 . 4704737 . 10.1371/journal.ppat.1005349 . free .
  41. Velu V, Shetty RD, Larsson M, Shankar EM . Role of PD-1 co-inhibitory pathway in HIV infection and potential therapeutic options . Retrovirology . 12 . 14 . February 2015 . 25756928 . 4340294 . 10.1186/s12977-015-0144-x . free .
  42. Baruch K, Deczkowska A, Rosenzweig N, Tsitsou-Kampeli A, Sharif AM, Matcovitch-Natan O, Kertser A, David E, Amit I, Schwartz M . PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease . en . Nature Medicine . 22 . 2 . 135–7 . February 2016 . 26779813 . 10.1038/nm.4022 . 20699898 .
  43. Kurnellas MP, Adams CM, Sobel RA, Steinman L, Rothbard JB . Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation . Science Translational Medicine . 5 . 179 . 179ra42 . April 2013 . 23552370 . 3684024 . 10.1126/scitranslmed.3005681 .
  44. Kurnellas MP, Ghosn EE, Schartner JM, Baker J, Rothbard JJ, Negrin RS, Herzenberg LA, Fathman CG, Steinman L, Rothbard JB . Amyloid fibrils activate B-1a lymphocytes to ameliorate inflammatory brain disease . Proceedings of the National Academy of Sciences of the United States of America . 112 . 49 . 15016–23 . December 2015 . 26621719 . 4679000 . 10.1073/pnas.1521206112 . 2015PNAS..11215016K . free .
  45. Kurnellas MP, Schartner JM, Fathman CG, Jagger A, Steinman L, Rothbard JB . Mechanisms of action of therapeutic amyloidogenic hexapeptides in amelioration of inflammatory brain disease . en . The Journal of Experimental Medicine . 211 . 9 . 1847–56 . August 2014 . 25073790 . 4144739 . 10.1084/jem.20140107 .

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