anti PD-1 antibody is coming back!!

[hahaha]

http://clincancerres.aacrjournals.org/cgi/content/abstract/14/10/3044

This is an experiment for cancer, but has also show good CD4 result.

Results: The study showed the antibody to be safe and well tolerated in this patient population. No single maximum tolerated dose was defined in this study. Clinical benefit was observed in 33% of the patients with one complete remission. Pharmacokinetic analyses show that serum Cmax and the AUC of CT-011 increased proportionally with dose. The median t1/2 of CT-011 ranged from 217 to 410 hours. Sustained elevation in the percentage of peripheral blood CD4+ lymphocytes was observed up to 21 days following CT-011 treatment.
Conclusions: A single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and well tolerated in patients with advanced hematologic malignancies.

[bimazek]

CT-011 is a humanized IgG1 monoclonal antibody that modulates the immune response through interaction with PD-1, a protein belonging to the B7 receptor family present on lymphocytes.  Chaim Sheba Medical Center, Tel Hashomer, Israel.   from the study above

this is very good news
i knew pd-1 was a star

[bimazek]

from national cancer institute website

anti-PD-1 monoclonal antibody CT-011
A humanized monoclonal antibody directed against human PD-1 (programmed cell death 1; PDCD1), with immunomodulating and antitumor activities. Anti-PD-1 monoclonal antibody CT-011 blocks interaction between the receptor PD-1 with its ligands, PD-1 ligand 1 (PD-1L1) and PD-1 ligand 2 (PD-1L2), resulting in the attenuation of apoptotic processes in lymphocytes, primarily effector/memory T cells, and the augmentation of the anti-tumor activities of NK cells. PD-1 is an inhibitory receptor belonging to the B7-receptor family that is expressed on lymphocytes and myeloid cells; its ligands, PD-1L1 and PD-1L2, are expressed not only by hematopoietic cells but also by cells in non-lymphoid tissues. Check for active clinical trials or closed clinical trials using this ag

[bimazek]

PD-1 in 2008

I have to say i was right about being excited about PD-1 ... look at the science articles on PD-1 just in 2008. !!!!!!!!!

PD-1 is turning out to be THE STAR OF THE SHOW, stepping out as major regulator of immune system!!!!!!!!!

It may be used in combo with vaccines or haart and be the key critical missing factor to solve hiv.

PD-1 "facilitate long-term viral control without resorting to lifelong drug therapy."

"It has recently been shown in a mouse model that a combination of therapeutic vaccination and blockade of PD-1  ... enhanced the function of responding T cells and significantly improved viral control ...  a similar strategy may enhance the response to therapeutic immunisation in HIV-1 infection and facilitate long-term viral control without resorting to lifelong drug therapy."

"Release from the inhibitory PD-1 pathway has been consistently achieved by antibodies to PD-1 in humans and non-human primates infected by human immunodeficiency virus-1 (HIV-1), resulting in enhancement of T-cell immune responses to HIV-1."

"Therapeutic vaccination is a potentially promising strategy to enhance T cell immunity and viral control in chronically infected individuals. ... we show that blocking programmed death (PD)-1/PD-L1 inhibitory signals on exhausted CD8+ T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8+ T cell responses and improves viral control in mice ....  Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors."

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
It has recently been shown in a murine model of lymphochoriomeningitis virus that a combination of therapeutic vaccination and blockade of PD-1's interaction with its ligand, PD-L1, both enhanced the function of responding T cells and significantly improved viral control [29]. Perhaps a similar strategy may enhance the response to therapeutic immunisation in early HIV-1 infection and facilitate long-term viral control without resorting to lifelong drug therapy.
A Way Forward
The human immune system is extraordinarily active against infection with HIV-1, yet never eliminates the virus and rarely controls viral replication for prolonged periods without the assistance of anti-retroviral therapy (ART). In order to harness the power of the human immune response in HIV therapy, we need a better understanding of the key elements of protective immunity against the virus and how and why these ultimately fail in chronic infection.
A New Study on Cytotoxic T Lymphocytes   Most investigators would nominate cytotoxic T lymphocytes (CTLs) as key players in the control of HIV-1 infection, based on data accumulated over the two decades since they were first described. This evidence includes the appearance of CTLs very early in HIV-1 infection coinciding with a profound drop in plasma viral load and the dramatic rise in viraemia following CTL depletion in monkey models of both acute and chronic infection with simian immunodeficiency virus  http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0050103
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

http://medicine.plosjournals.org/archive/1549-1676/5/5/figure/10.1371_journal.pmed.0050103.g001-L.jpg?SESSID=4b2631c538ffd4b227ccf5ba2365cda9

Twelve immunotherapy drugs that could cure cancers. - Programmed death-1 (PD-1) is a negative regulator of T-cell function
(32-38). Blocking PD-1 can increase anti-tumor T-cell immunity
Twelve immunotherapy drugs that could cure cancers.
Review article
Immunological Reviews. 222(1):357-368, April 2008.
'Mac' Cheever, Martin A. 1
Abstract:
Summary: Immune T cells can kill cancer cells. Cancer vaccines function by increasing the number of immune T cells. There are exceedingly strict biologic limits imposed on the immune system to prevent excessive T-cell activation and expansion. The same biological restrictions limit cancer vaccines. Immunotherapeutic agents that circumvent the biological restrictions have been invented and formulated, including (i) dendritic cell activators and growth factors, (ii) vaccine adjuvants, (iii) T-cell stimulators and growth factors, (iv) immune checkpoint inhibitors, and (v) agents to neutralize or inhibit suppressive cells, cytokines, and enzymes. Few of these agents are broadly available for the development of effective multiple component regimens. The major problem facing immunotherapy today is a lack of broad availability of agents already in existence. The National Cancer Institute has developed a well-vetted ranked list of agents with high potential to serve as immunotherapeutic drugs. This review focuses on 12 of the agents, all with proven ability to augment T-cell responses. Alone, each has little chance of making substantial inroads into cancer therapy. In combinations dictated by biology, the agents are overwhelmingly likely to have an impact. Future availability of these agents for development of innovative combination cancer therapy regimens will provide a benchmark for the resolve of the national cancer therapy translational research enterprise.
http://pt.wkhealth.com/pt/re/immr/abstract.00004210-200804000-00024.htm;jsessionid=LRNfrnPHc8qg4L023mv2vm3rJz7x7jlG98cb4NW2hXLyCJrLgLgg!80218374!181195629!8091!-1


http://www.blackwell-synergy.com/action/showFullText?submitFullText=Full+Text+HTML&doi=10.1111%2Fj.1365-2567.2007.02780.x&cookieSet=1
      Mucosal Immunology Unit, Kings College London at Guy’s Hospital, Guy’s Hospital, London, UK
Dr T. Lehner, Mucosal Immunology Unit, Kings College London at Guy’s Hospital, Guy’s Tower 28th Floor, Guy’s Hospital, London SE1 9RT, UK. Email: thomas.lehner@kcl.ac.uk
Summary
The original concept of contrasuppression (CS) is evident in many immunoregulatory mechanisms. Inhibition of suppressor activity – CS – may be critical in microbial infection and autoimmunity. The major cellular interactions involved in suppression are the CD25+ FoxP3+ CD4+ T regulatory cells, programmed death-1 (PD-1) : PD-L1/L2 and cytotoxic T lymphocyte antigen-4 (CTLA-4) : CD80/86 pathways. These cellular functions are affected by dendritic cells (DC) and a complex array of cytokines of which interleukin (IL)-2, IL-10, IL-6 and transforming growth factor-ß (TGF-ß) are especially significant. Inhibition of regulatory cells, suppressor pathways or cytokines, is consistent with CS and can be attributed to IL-6, IL-2, PD-1 or PD-L-1 antibodies, blockade of CTLA-4 : CD80/86 pathway, inhibition of CD40–CD40L pathways, and TGF-ß, IL-10 antibodies. Contrasuppression may regulate innate immunity by Toll-like receptor expressed not only in non-cognate DC, monocytes, natural killer cells and ?d T cells but also in adaptive T cells. Furthermore, cross-talk between innate and adaptive immunity may be facilitated by contrasuppressor activity.
‘‘What’s in a name?
That which we call a rose by any other name would smell as sweet.’’ From Romeo and Juliet (II, 47–8) W. Shakespeare


http://www.jem.org/cgi/content/abstract/jem;205/3/543
Therapeutic vaccination is a potentially promising strategy to enhance T cell immunity and viral control in chronically infected individuals. However, therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral T cell responses has not always been observed. One of the principal reasons for the limited success of therapeutic vaccination is that virus-specific T cells become functionally exhausted during chronic infections. We now provide a novel strategy for enhancing the efficacy of therapeutic vaccines. In this study, we show that blocking programmed death (PD)-1/PD-L1 inhibitory signals on exhausted CD8+ T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8+ T cell responses and improves viral control in mice chronically infected with lymphocytic choriomeningitis virus. This combinatorial therapeutic vaccination was effective even in the absence of CD4+ T cell help. Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors.


Release from the inhibitory PD-1– PD-L1 pathway has been consistently achieved by antibodies to PD-1 or PD-L1 in humans and non-human primates infected by human immunodeficiency virus-1 (HIV-1), resulting in enhancement of T-cell immune responses to HIV-1.



Twelve immunotherapy drugs that could cure cancers. - all 4 versions »
MA Mac'Cheever - Immunological Reviews, 2008 - pt.wkhealth.com
... Programmed death-1 (PD-1) is a negative regulator of T-cell function
(32-38). Blocking PD-1 can increase anti-tumor T-cell immunity. ..

Resisting Immune Exhaustion in HIV-1 Infection
S Rowland-Jones, T de Silva - PLoS Med, 2008 - medicine.plosjournals.org
... Abbreviations: ART, anti-retroviral therapy; CTL, cytotoxic T lymphocyte; IL-2,
interleukin-2; PD-1, programmed death-1; STI, structured treatment interruption.

T-cell responses in primary HIV-1 infection.
H Streeck, D van Bockel, A Kelleher - Current Opinion in HIV & AIDS, 2008 - co-hivandaids.com
... Recent findings: Recent studies have revealed early dysfunction of T cells
demonstrating increased expression of PD-1, CTLA-4 and reduced expression of CD127

http://scholar.google.com/scholar?as_q=&num=100&btnG=Search+Scholar&as_epq=pd+1&as_oq=&as_eq=&as_occt=any&as_sauthors=&as_publication=&as_ylo=2008&as_yhi=2008&as_allsubj=some&as_subj=med&hl=en&lr=

… display distinct differentiation phenotypes but have similar level of PD-1 expression in healthy … - all 2 versions »  XH He, QT Jia, FY Li, M Saltis, Y Liu, LH Xu, QB … - Clinical Immunology, 2008 - Elsevier
... CD8 + T cells specific for both persistent and non-persistent virus at different
differentiation stages express moderate levels of PD-1 molecules. ...
Cited by 1 - 

Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic … - all 3 versions »SJ Ha, SN Mueller, EJ Wherry, DL Barber, RD Aubert … - Journal of Experimental Medicine, 2008 - Rockefeller Univ Press... Enhancing therapeutic vaccination by blocking PD-1–mediated inhibitory signals during
chronic infection Sang-Jun Ha 1 , Scott N. Mueller 1 , E. John Wherry 1 ...

Special regulatory T cell review: The resurgence of the concept of contrasuppression in … - all 4 versions »
T Lehner - Immunology, 2008 - Blackwell Synergy... PD-1–PD-L1 inhibitory pathway in immunoregulation. Programmed death-1 (PD-1) is a transmembrane protein similar to CTLA-4, but does not bind to CD80 or CD86. ...Cited by 1 -   - BL Direct

Antigen Load and Viral Sequence Diversification Determine the Functional Profile of HIV-1–Specific …
H Streeck, ZL Brumme, M Anastario, KW Cohen, JS … - PLoS Med, 2008 - medicine.plosjournals.org
... Assessing CD127 Frequency and PD-1 Expression on Epitope-Specific (Tetramer-Positive)
CD8 + T Cells. Cryopreserved PBMCs were processed as described above. ...
Cited by 1 -   


Genetic complexity of autoimmune myocarditis - all 2 versions »
HS Li, DL Ligons, NR Rose - Autoimmunity Reviews, 2008 - Elsevier
... Blockade of signaling through specific genes, such as CTLA4, ICOS and PD-1, can
either enhance or prevent the development of experimental autoimmune myocarditis


Twelve immunotherapy drugs that could cure cancers. - all 4 versions »
MA Mac'Cheever - Immunological Reviews, 2008 - pt.wkhealth.com
... Programmed death-1 (PD-1) is a negative regulator of T-cell function
(32-38). Blocking PD-1 can increase anti-tumor T-cell immunity

Variable patterns of programmed death-1 (PD-1) expression on fully functional memory T cells …
DG Bowen, NH Shoukry, A Grakoui, MJ Fuller, AG … - J Virol, 2008 - ncbi.nlm.nih.gov
Variable patterns of programmed death-1 (PD-1) expression on fully functional memory
T cells following spontaneous resolution of hepatitis C virus infection

The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus … - all 3 versions » E Lazar-Molnar, A Gacser, GJ Freeman, SC Almo, SG … - Proceedings of the National Academy of Sciences, 2008 - National Acad Sciences  ... BIOLOGICAL SCIENCES / MICROBIOLOGY The PD-1/PD-L costimulatory pathway critically  affects host resistance to the pathogenic fungus Histoplasma capsulatum

Resisting Immune Exhaustion in HIV-1 Infection
S Rowland-Jones, T de Silva - PLoS Med, 2008 - medicine.plosjournals.org
... Abbreviations: ART, anti-retroviral therapy; CTL, cytotoxic T lymphocyte; IL-2,
interleukin-2; PD-1, programmed death-1; STI, structured treatment interruption

[bimazek]

"[ALL] therapeutic vaccine designed to [stop] HIV ... will need to overcome or circumvent the challenge posed by the inability of certain exhausted B cells to make high-quality antibodies." 

What this means is that all the vaccines tried up to now probably failed for this reason... the CD4, CD8 and B cells were all exhausted (PD-1 and CTLA, i believe) and this must be discovered as to how to fix this problem, i suggest anti-pd-1 monoclonal antibodies etc....

in any case it is a huge step forward for vaccines and gene therapy and hiv science, each week brings giant new insights

NIAID's HIV vaccine research program aims to increase the understanding of B cells to help inform the development of an effective vaccine, and this study contributes to this effort. The authors note that the design of a therapeutic vaccine designed to slow HIV disease progression will need to overcome or circumvent the challenge posed by the inability of certain exhausted B cells to make high-quality antibodies.   http://www.sciencedaily.com/releases/2008/07/080714092726.htm

Now, researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have shown that a similar type of exhaustion strikes another important brigade of immune system soldiers: the B cells that make virus-fighting proteins called antibodies.  Recent studies have shown that HIV causes a vigorous and prolonged immune response that eventually leads to the exhaustion of key immune system cells--CD4+ and CD8+ T-cells--that target HIV. These tired cells become less and less able to fight the virus, and the cells' fatigue contributes to the inability of an HIV-infected person's immune system to clear the virus from the body.

http://www.jem.org/cgi/content/abstract/jem.20072683v1

July 14, 2008
doi:10.1084/jem.20072683
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Moir et al.
Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals

Susan Moir1, Jason Ho1, Angela Malaspina1, Wei Wang1, Angela C. DiPoto1, Marie A. O'Shea1, Gregg Roby1, Shyam Kottilil1, James Arthos1, Michael A. Proschan2, Tae-Wook Chun1, and Anthony S. Fauci1

1 Laboratory of Immunoregulation and 2 Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, MD 20892

Human immunodeficiency virus (HIV) disease leads to impaired B cell and antibody responses through mechanisms that remain poorly defined. A unique memory B cell subpopulation (CD20hi/CD27lo/CD21lo) in human tonsillar tissues was recently defined by the expression of the inhibitory receptor Fc-receptor-like-4 (FCRL4). In this study, we describe a similar B cell subpopulation in the blood of HIV-viremic individuals. FCRL4 expression was increased on B cells of HIV-viremic compared with HIV-aviremic and HIV-negative individuals. It was enriched on B cells with a tissuelike memory phenotype (CD20hi/CD27–/CD21lo) when compared with B cells with a classical memory (CD27+) or naive (CD27–/CD21hi) B cell phenotype. Tissuelike memory B cells expressed patterns of homing and inhibitory receptors similar to those described for antigen-specific T cell exhaustion. The tissuelike memory B cells proliferated poorly in response to B cell stimuli, which is consistent with high-level expression of multiple inhibitory receptors. Immunoglobulin diversities and replication histories were lower in tissuelike, compared with classical, memory B cells, which is consistent with premature exhaustion. Strikingly, HIV-specific responses were enriched in these exhausted tissuelike memory B cells, whereas total immunoglobulin and influenza-specific responses were enriched in classical memory B cells. These data suggest that HIV-associated premature exhaustion of B cells may contribute to poor antibody responses against HIV in infected individuals.

---------- this paper is so complicated that i can barely understand it but basically i think it says that in tonsils and other immune nodes things get so confused and turned off and exhausted (probably pd-1 but i havent read full article)  that no wonder all the vaccines fail, once hiv is in system the cd4, 8 and B cells get messed up big time, my question are...

if a person is on haart and they start before the immune system is damaged and thier system rebounds to levels of CD4 cells of 600 800 900 1000 or 1200 basically functioning immune system
How much damage is still present vis a vie the exhaused cd4, 8 and B cells -- do these rebound?
well they must because if you go off of haart for a year or two it takes months for the immune system to get worn down again

but what about the B cells
and how is exhausted cells effect vaccines

can someone get into and post the results and discussion at the end of this paper... i dont have the access to this journal

[bimazek]

http://www.newswise.com/articles/view/544309/

Researchers Invigorate “Exhausted” Immune Cells: Findings Support New Therapies for HIV, Hepatitis, Cancer
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Medical News       Keywords
IMMUNOLOGY, HIV, HEPATITIS B, HEPATITIS C, CANCER, T CELLS, CHRONIC INFECTION, DRUG, MELANOMA, THERAPY, IMMUNE SYSTEM

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Description
In battles against chronic infections, the body’s key immune cells often become exhausted and ineffective. Researchers at The Wistar Institute have found a way to restore vigor to these killer T cells by blocking a key receptor on their surface, findings that may advance the development of new therapies for diseases such as HIV, hepatitis B and C, and cancer.

Newswise — In battles against chronic infections, the body’s key immune cells often become exhausted and ineffective. Researchers at The Wistar Institute have found a way to restore vigor to these killer T cells by blocking a key receptor on their surface, findings that may advance the development of new therapies for diseases such as HIV, hepatitis B and C, and cancer.

In their study, published online September 15 in the Proceedings of the National Academy of Sciences (PNAS), Wistar Institute investigators and colleagues report that using an antibody to block the receptor, known as programmed death-1 (PD-1), dramatically restored immunity in chronically infected mice. Furthermore, they discovered a method to distinguish between T cells that can be revitalized in this way and those that can’t.

The findings will help researchers develop PD-1 blocking agents, and also provide a way to select patients who may benefit most from such novel drugs, says the study’s lead author E. John Wherry, Ph.D., an assistant professor in Wistar’s Immunology Program.

“Blocking PD-1 may provide a novel tool to fight chronic infection as well as some cancers, like melanoma, that are susceptible to destruction by the immune system,” Wherry said. Examples of infections that often result in T-cell exhaustion are HIV, hepatitis B, and hepatitis C, he says.

Wherry’s continuing research on PD-1 has provided the groundwork for developing antibody therapies that inhibit the receptor. Wherry says he knows of a pharmaceutical company preparing to test one of these agents in patients with hepatitis C.

Researchers have known that T cells – white blood cells capable of inducing the death of infected or cancerous cells – become progressively less functional over time. In earlier studies, Wherry and his colleagues found that, during the course of a chronic infection, gene expression in killer T cells changed dramatically as the cells became exhausted and immune response to a pathogen slowed down. Wistar investigators then identified one gene that played a central role in this tamping down of immune response – PD-1, which produces PD-1 protein receptors that stud the surface of these T cells.

In follow-up experiments, they found that if they blocked PD-1 receptors in cell cultures using an antibody made up of one of the protein’s natural binding ligands they could alleviate T-cell exhaustion. This demonstrated that PD-1 serves as a “brake” on T-cell function.

Wherry suspects that this reaction is designed to protect a body against the ravages that a chronically over-stimulated immune system can wreak. “The immune system can cause a lot of damage in an effort to control an infection. If you can’t clear an infection and are making yourself sick trying to do so, it may be better off to live with the infection than die from the immune-mediated collateral damage,” he said.

In the current study, Wherry and colleagues tested in mice infected with lymphocytic choriomeningitis virus the effect of plugging the PD-1 receptor with the antibody, thus releasing the “brake” on the immune system. And they studied two different subsets of killer T cells: those with the highest expression of PD-1 receptors and ones with an “intermediate” expression. Researchers theorized that those T cells with the highest PD-1 expression, signifying the deepest exhaustion, would benefit most from an antibody to PD-1.

To their surprise, that is not what they found. They implanted these two different subsets of cells into infected mice, and then gave the mice a PD-1 antibody. Those mice implanted with T cells with intermediate expression of PD-1 recovered their vigor, while mice with the highest PD-1 expression did not. “It may be the killer T cells expressing a lot more PD-1 are already committed to cell death,” Wherry said.

Knowing which subset of T cells will respond to an antibody drug will help physicians identify patients who could respond, if these novel agents reach extensive clinical testing, Wherry says. “We can optimize the promise of such a medical tool and minimize wasteful treatment,” he said.

Wherry says this study provides insights into how potential PD-1 agents can be refined so as not to provoke an autoimmune response, in which the body errantly attacks its own tissue. And in the same way, it suggests strategies by which to disarm autoimmune disorders, such as lupus, he says. “If we can understand how to turn PD-1 off to enhance immunity, this will provide insights on how to turn it on to treat autoimmune disorders,” Wherry said.

Wistar’s Shawn D. Blackburn and Haina Shin assisted with the study, along with Gordon J. Freeman, Ph.D., of the Dana-Farber Cancer Center.

[bimazek]

30 more pd-1 papers published in last year!! and new results expected in vivo to be published within the next 6-12 months. "Those papers will be extremely critical in taking [the research] to the next step," also some meds already in development for repressing the immune system using pd-1 in opposite way as needed for hiv for immune suppression, also found that pd-1 is important in b-cell dysfunction(b cells can get at reservoirs hopefully)

http://www.the-scientist.com/article/display/55036/
excerpts

But before investigating molecular mechanisms, researchers are focused on turning the research into therapy. The next step is to determine the side effects of blocking the PD-1 pathway in vivo. "All indications are if you block it, the immune system will be more active. The big question is if you do that, is it safe?" says Freeman. Ahmed and his team are beginning experiments in non-human primates with SIV. He expects results on in vivo blockades to be published within the next 6-12 months. "Those papers will be extremely critical in taking [the research] to the next step," says Ahmed.

This also may explain the greater immune salvaging effect of an anti-PD-L1 blockade compared to an anti-PD-L2 blockade, a result previously attributed to differential expression of the molecules.

Also, this past July researchers revealed the crystal structures of the PD-1/PD-L1 and PD-1/PD-L2 complexes. 6,7 The structural data shows the binding interfaces between PD-1 and its two ligands, vital information for developing improved ways to manipulate their interaction: Some research groups are already using this structural data to develop ligands with higher affinity as immunosuppressants, says Freeman.

But before investigating molecular mechanisms, researchers are focused on turning the research into therapy. The next step is to determine the side effects of blocking the PD-1 pathway in vivo. "All indications are if you block it, the immune system will be more active. The big question is if you do that, is it safe?" says Freeman. Ahmed and his team are beginning experiments in non-human primates with SIV. He expects results on in vivo blockades to be published within the next 6-12 months. "Those papers will be extremely critical in taking [the research] to the next step," says Ahmed.


Walker's investigation found that blocking the pathway with an antibody to PD-L1 restored function to exhausted T cells in vitro. "The results from the HIV study were very robust and very exciting," says John Wherry, a co-author on the paper from the Wistar Institute in Philadelphia. Shortly after, many labs began HIV studies of PD-1, says Wherry, and the data began piling up.


Other inhibitors
In 30 to 40 subsequent papers, says Ahmed, upregulated expression of the PD-1 pathway has been firmly documented as a mechanism of T cell dysfunction in the three main human chronic viral infections - HIV, hepatitis B, and hepatitis C - as well as SIV infection in non-human primates.

Further investigations of PD-1 expression on exhausted T cells led to the discovery of a plethora of inhibitory pathways active during chronic infection. Last year, Ahmed and Wherry examined the molecular signature of T cell exhaustion by comparing gene expression profiles of infected and functional CD8 T cells in mice. 3 Microarray data not only revealed "striking" levels of PD-1 expression on the chronically infected T cells, says Wherry, but expression of a whole set of inhibitory genes, including those for known inhibitory receptors like 2B4, Ly49 family members, and GP49B. "The immune system has evolved multiple layers of negative regulation," says Wherry.


http://www.the-scientist.com/article/display/55036/

Programmed death I (PD-1), an inhibitory receptor on immune system cells, has long been known to play an important dual role in immune regulation: Preventing the immune system from attacking the self and keeping an activated immune system in check.

In 2006, however, Rafi Ahmed, of the Emory University School of Medicine, and colleagues discovered that the PD-1 pathway could also be exploited by pathogens to repress normal T cell function during chronic viral infection. In mice infected with lymphocytic choriomeningitis virus (LCMV), Ahmed found PD-1 upregulated in functionally-impaired CD8 T cells. The team then showed that preventing PD-1 activation by blocking its ligands with antibodies restored T cell function and decreased viral load in the mice. 1 Scientists had previously believed that T cells suffered irreversible dysfunction during chronic disease. Suddenly, there was the possibility of rescue.

The research was immediately extended to human chronic viral disease. Seven months after Ahmed's paper was published, a team of researchers led by Bruce Walker at Partners AIDS Research Center (PARC) in Boston published this month's Hot Paper. They showed that PD-1 is up-regulated on the surface of T cells cultured from individuals infected with HIV, and its expression correlates positively with viral load and inversely with CD4 T cell count. 2 T cells that unsuccessfully attack the virus start to express high amounts of PD-1, says Gordon Freeman, a professor of medicine at Harvard Medical School and co-author on the paper. "It's like putting a red flag on a T cell saying bind me and stop me;" once PD-1 is expressed, ligands PD-L1 and PD-L2 bind the receptor, activating inhibitory signals in the cell.

As in Ahmed's study, Walker's investigation found that blocking the pathway with an antibody to PD-L1 restored function to exhausted T cells in vitro. "The results from the HIV study were very robust and very exciting," says John Wherry, a co-author on the paper from the Wistar Institute in Philadelphia. Shortly after, many labs began HIV studies of PD-1, says Wherry, and the data began piling up.


Other inhibitors
In 30 to 40 subsequent papers, says Ahmed, upregulated expression of the PD-1 pathway has been firmly documented as a mechanism of T cell dysfunction in the three main human chronic viral infections - HIV, hepatitis B, and hepatitis C - as well as SIV infection in non-human primates.

Further investigations of PD-1 expression on exhausted T cells led to the discovery of a plethora of inhibitory pathways active during chronic infection. Last year, Ahmed and Wherry examined the molecular signature of T cell exhaustion by comparing gene expression profiles of infected and functional CD8 T cells in mice. 3 Microarray data not only revealed "striking" levels of PD-1 expression on the chronically infected T cells, says Wherry, but expression of a whole set of inhibitory genes, including those for known inhibitory receptors like 2B4, Ly49 family members, and GP49B. "The immune system has evolved multiple layers of negative regulation," says Wherry.

Around the same time, researchers identified a second reversible pathway involved in HIV T cell inhibition. 4 In the study, Daniel Kaufmann, an instructor at PARC, and colleagues showed that blocking CTLA-4, another inhibitory immunoregulatory receptor, can also reverse T cell dysfunction in chronic infection. They noted that in HIV infection, CTLA-4 is selectively upregulated in CD4 T cells but not CD8 cells, demonstrating that different types of T cells utilize different combinations of inhibitory pathways.


Missing pieces
How PD-1 blocks T cell activation is still an open question, says Ahmed. Researchers know that PD-1 has two tyrosine molecules on its cytoplasmic tail that get phosphorylated when PD-1 binds a ligand. The tail then binds phosphatases in the T cell, triggering a downregulation of antigen receptor signaling. But few additional details are known, says Freeman.

Recent research seems only to be further muddying the waters. Last year Freeman and colleagues implicated an additional co-stimulatory molecule in the inhibition pathway, B7-1. 5 B7-1 binds the PD-1 ligand, PD-L1, as well and also induces an inhibitory signal in T cells. This suggests that B7-1 and PD-1 may compete for binding of PD-L1. "It complicates the whole pathway in vitro," says Ahmed. Freeman agrees, and notes that because PD-L1 binds two inhibitory receptors, it may play a more crucial role in immune response than previously believed. This also may explain the greater immune salvaging effect of an anti-PD-L1 blockade compared to an anti-PD-L2 blockade, a result previously attributed to differential expression of the molecules.

Also, this past July researchers revealed the crystal structures of the PD-1/PD-L1 and PD-1/PD-L2 complexes. 6,7 The structural data shows the binding interfaces between PD-1 and its two ligands, vital information for developing improved ways to manipulate their interaction: Some research groups are already using this structural data to develop ligands with higher affinity as immunosuppressants, says Freeman.

But before investigating molecular mechanisms, researchers are focused on turning the research into therapy. The next step is to determine the side effects of blocking the PD-1 pathway in vivo. "All indications are if you block it, the immune system will be more active. The big question is if you do that, is it safe?" says Freeman. Ahmed and his team are beginning experiments in non-human primates with SIV. He expects results on in vivo blockades to be published within the next 6-12 months. "Those papers will be extremely critical in taking [the research] to the next step," says Ahmed.

Data derived from the Science Watch/Hot Papers database and the Web of Science (Thomson ISI) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age.
C.L. Day et al., "PD-1 expression on HIV-specific T cells is associated with T cell exhaustion and disease progression," Nature, 443:350-4, 2006. (Cited in 201 papers)


References
1. D.L. Barber et al., "Restoring function in exhausted CD8 T cells during chronic viral infection," Nature, 439:682-7, 2006.
2. C.L. Day et al., "PD-1 expression on HIV-specific T cells is associated with T cell exhaustion and disease progression," Nature, 443:350-4, 2006. (Cited in 201 papers)
3. E.J. Wherry et al., "Molecular signature of CD8+ T cell exhaustion during chronic viral infection," Immunity, 27:670-84, 2007.
4. D.E. Kaufmann et al., "Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction," Nat Immunol, 8:1246-54, 2007.
5. M.J. Butte et al., "Programmed Death-1 Ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses," Immunity, 27:111-22, 2007.
6. D.Y. Lin et al., "The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors," Proc Natl Acad Sci, 105:3011-6, 2008.
7. E. Lazar-Molnar et al., "Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2," Proc Natl Acad Sci, 105:10483-8, 2008.
 

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comment:
PD-1.PD-1L axis also important in cancer immunoescape
by anonymous poster

[Comment posted 2008-10-16 12:30:29]

it's not just being studied for chronic viral infections

[veritas]

Bimazek,

It looks like anti-pd is already in the clinic for cancer:


http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2008/05/first-human-ant.html

[David Evans]

It would seem that there's certainly good reason to hope that this translates into something hopeful for HIV. I'm neither an immunologist, nor an oncologist, but the scientists I respect greatly have taught me to simultaneously maintain hope and cheer on good science, while also maintaining healthy skepticism.

In this case, it would certainly seem that up-regulation of PD1 on CD4 cells, like that found by Bruce Walker and others is meaningful. Particularly, the fact that the more virus a person has, the the more likely their CD4 cells are to express PD1 - and therefore more likely to be suppressed in their ability to respond to infection. Clearly, there should be more research to understand how PD1 plays a role in immune disregulation.

I remain, however, a tad cautious about jumping from this finding to the conclusion that artificially trying to suppress PD1 by creating antibodies to PD1 is a good idea. The brightest immunologists in the world have been continuously humiliated by the complexity of the immune response to HIV. Specifically, one of the most frustating elements of HIV is the fact that there is rock solid evidence for two contradictory and paradoxical situations: there are signs of both over-activation and immune suppression. It may turn out that intervening in regards to PD1 (with or without ARV drugs) restores a healthy balance to the immune system. It could also turn out that PD1 antibodies don't accomplish anything meaninful, or throw things even more out of balance.

I'm genuinely looking forward (in a hopeful manner) to more research in this area.

Respectfully,
David

[leit]

I remain, however, a tad cautious about jumping from this finding to the conclusion that artificially trying to suppress PD1 by creating antibodies to PD1 is a good idea.

Your opinion ends up by agreeing with the one expressed by Guido Silvestri at the last IAC in his excellent talk (from page 43):

"The second point is that yes the immune system, the immune response have the capability of controlling virus replication in a lot of systems has been shown. But also have this potential to damage immune system by creating more targets for a virus and also by inducing a chronic exhaustion, a chronic detrition of the ability to respond.
And this has been shown actually in some experiments where compounds like IL15 or antibody against CTLA4 were given in an attempt to boost the immune responses against the virus with the paradoxical effect of seeing an increase in virus replication occurring. And that is why I am a little bit skeptical for instance of proposing to block PD1 or PDl system as a way to suppress virus replication in vivo."

It was very interesting also the rightly provocative remark about immmunosuppressants by the activist Mark Milano (page 56):

MARK MILANO: Mark Milano [misspelled?] with Dicria [misspelled?] and Health Gap. I absolutely think there is a way to deal with immune activation. Your talk is really deja vu. I have been to every AIDS conference since '89, and at virtually every conference someone speaks about immune activation as being the cause. Anthony Fauci has spoken about it a number of times.
And I always get up and say, I have been living with HIV since 81, I controlled it for 26 years with no antiretrovirals by using alternate day prednisone since 85 for a different condition. And I had very high virania, over- close to a million for 5 years and yet my CD4 counts stayed completely stable at 4 to 500 just like a Sooty mangabey and with no side effects whatsoever, a clear case, I think, of immune suppression, low grade, controlling immune activation and yet for 15 years I have said, let us look at this.
No one will study it. People refuse to give a drug like prednisone or any other immmunosuppressant to people with HIV. They will not do it. How do we get this studied when I know there are more people than just me who have been taking prednisone and have been able to control their HIV pathogenesis without antiretrovirals? How do we get a study? What do we do? It is very frustrating. You are not the first person to say this.

GUIDO SILVESTRI, M.D.: Amen. That is all I can say. I agree with you, obviously you need to understand that the regulatory agencies like FDA are cautious. There have been some studies. Mike Letterman did some cyclosporine experiments. Jeffrey Pantilare [misspelled?] did some microphentilate. There are obviously some caution by regulatory agencies when it comes to giving potent immunosuppressants to individual with an immunodeficiency. But I agree with you, I think it is something that ought to be explored.

MARK MILANO: Some day.

[brazilianman]

e-mail for medearex


Hello I am a Brazilian NGO that cares for HIV positive and is impressed with the results of studies of antibodies anti-CTLA4 - MDX-1106 , would be a treatment for HIV or is only a hypothesis? I read a study where monkeys were better with this antibodyMDX-1106.
 anti-CTLA4  phase III brings results? thank you very much. sorry bad english, I look forward provided email.

[brazilianman]

medearex

 he is nothing