| 1 | ICU_Dr.Pradeep Rangappa | Immunomodulation in Sepsis | Dr. Pradeep Rangappa | 980 | 31 | 2 | 46.7 | positive | 23:39 | So, friends, so thanks for having me for this meet. So the topic that I would be talking on is, um, Immuno modulation in sepsis, do we really need the, Immuno modulation? So it's a very interesting topic. So I'll just give you a fair overview on what are the new concepts in Immuno modulation and then have a discussion on this. So when we look at the infection. So this is always associated with an immune response from the body. And generally there is a good balance with regards to the infection and the type of immune response of the body mounts. So if there is an inadequate immunity, then the infection obviously gets overwhelming and that leads to problems. And when there is complete dissonance of this immunity, then the organ dysfunction happens and a possible death or bad outcome would happen. So this is what typically happens in sepsis. So when you look at immune homeostasis, which means there is a perfect balance between the infection and the type of response that the body elicits for the infection. So when you look at this nice pictorial diagram, so when there is an infection, so there is this Neutrophil migration that happens into the tissues. And these sort of neutrophils are counted by, of these neutrophils, counter these microbes, the errands of pathogens happen by this Neutrophil migration. And these microfids get activated and there is phagocytosis of these microbes that happen. So this is what typically happens. And there are these B cells that you see in the bloodstream, which mounts antibodies to these pathogens. So this is a typical garden sort of a variety of homeostasis that prevails whenever we get affected with infections. So what happens when there is a immune dissonance or when there is a immune dysregulation? So we see there is a problem. So there is this Neutrophil migration and there is this sort of a Neutrophil migration that happens, which counters the microbes. Alongs to it, there is the whole sort of a cytokine, sort of a tsunami that happens. You can see this is the whole cytokine storm that happens. And alongs to it, there is a disregulated sort of an immune response that leads to loss of this endothelial integrity and the cell death that you see here. So this is what and there is this damage associated proteins or metaloprotinases that get released because of this dead cells. So this is an immune dysregulation that typically tends to happen in sepsis. So and the quantum of this has led to the new definition of sepsis, even the new sepsis definition that is come out recently has retained the definition, which is life-threatening organ dysfunction. And there is whole sort of an emphasis given to disregulated host response to the infection, which means the host is not mounting a regulated response to the infection and it is totally disregulated that leads to organ dysfunction. And that is associated with the organ dysfunction which leads to mortality and when septic shock, the mortality is up to more than 40% is what we have understood. So now the whole question remains and what is the link between this disregulation that happens and what is the role of immunity in this? So this is what we are here to deliberate upon. So we understand that adequate immune response is needed to fight the infection, not leading to sepsis and what are the key determinants of this immunity? So one is the virulence of the bugs. So the cell wall components or extracellular proteins from the microbes determine how badly the infection occurs and the immune dysregulation can happen. And then the individual, the host has different types of immunity, one is the innate immunity, one is the acquired immunity and the whole genetic profile of an individual which influences what sort of an immune response that he would mount to an infection. So this also is a very important entity. And these two determine the type of the cytokinesctorm or the type of lupotrymstorm or the type of sort of a immune dissonance that happens. And it is also dependent on how effectively vascular integrity is making. Now the whole renewed emphasis is on the vascular integrity which gets derailed or derailed as the first aspect. And that is what leads to the dead cells and the release of damp, which is the damage associated metaloprotinases. And so there is now the whole emphasis on the endothelial integrity. So the migration of neutrophils, endothelial integrity and the inflammatory process within the vascular endothelium is what determines the type of dissonance or immune dissonance that tends to happen. So when you look at the clinical phases of sepsis, there is one commonality between the presepsis, the acute phase of the sepsis and the recovery phase. So in presepsis, the immune program that the host has within him in a milieu determines his response to the infection. Along with this, we have recognized age has a bearing, comorbidity on which we do not have control has a bearing, the frailty of an individual has a brailing and the environmental factors in the acute phase, which means when the subsist has already set in the, there also you have this immune programming within the body, which influences the type of response along with it the virulence of the birth and the organ dysfunction or the vulnerability of the organs, we tend to get affected or dysfunctional matters. And the clinical context and his interventions within the ICU, all these determines how the individual or the patient responds to the acute phase of the sepsis. And in the recovery phase, also, immune program is needed as to how effectively the tsunami or the cytokine storm is handled at the recovery process or the organ dysfunction tends to get better. And the duration of illness, the complications that have occurred during the ICU or during the sepsis and the hospital exposure. So this is, so if you see the common aspect between the presepsis, acute and the recovery phase remains the immune program or the immune makeup or the internal milieu of an individual, which influences how effectively the recovery happens. When you look at this diagram, what has been interestingly shown by these Irish authors is 10% of the deaths in sepsis happen due to intense inflammatory phase, which happens in the early part of the system. In early part, there is this inflammatory response and to mitigate that, we may use not of interventions and some of which is in food steroids, which may help to mitigate this inflammatory response. And only 10% of the deaths tend to happen in the acute phase. And it is shown that the 30% of the deaths happen in the later part of the sepsis where a profound immune suppression happens, which we call it by various terms as immune paralysis or compensated anti-inflammatory response syndrome or chias or post-sepsis syndrome. And here, immune suppression is what is the patient, which means to say the predominant deaths in sepsis happen in the later phase where the immune suppression has set in. And this is where the whole concept of immune chemostasis comes. And we could effectively save patients. So since more deaths happen in the immune suppressive phase, interventions have to be targeted in this phase to save the patients. And this is what we call it as immune homoagesis. And if you look at the cytokine storm and the correlation to sepsis in COVID or in non-COVID, it has been shown that the cytokine storm is really a serious entity. And it tends to prevail more often in sepsis and sepsis with the RDS, it is lot more common than in other conditions, which goes on to show that yes, cytokine storm and cytokines have a bearing in influencing the outcome in the sepsis patients. So let us look now at the whole sort of a gamut or the cosmic sort of a disturbances that tend to happen within the body by all these immune mechanisms. So these are all the beautiful cells that have a bearing on the immune cells. There are dendrite cells, there are T cells, there are B cells, there are neutrophils, there are microfagers. And there are these myeloid derives of the surface. So all these have a bearing on how they influence the immune makeup of an individual. So what have we understood by sepsis-induced immunosuppression? It is shown that in the post-sepsis phase or post-acute phase, there is something called epigenetic regulation, which happens within the cell. And there is sort of an energy failure within the, which means the cells become fatigue and the cells do not mount a good response. And because of these changes, there is some genetic regulation that happens with the fatigue yourselves. There is increased tolerance to the endotoxyl, which means they do not sort of mount a response to the endotoxyl. And these cells because they are fatigue, they are suppressed and there is no energy, they are more prone for apoptosis or pro-transal death. And it is shown that in the post-sepsis, there is impaired clearance of these microbes by these neutrophils. There is more production of the active oxygen species. And there is reduced migration. So the neutrophils also get fatigue and they don't migrate to the baspler endothelium and to the site where the infection. So there is reduced movement of these neutrophils. And it is also shown in the post-sepsis, there is reduction in the natural killer cells. And there are high alterations that happen in the natural killer cells. And there is reduced production of interferon dharma, which is protective by these natural killer cells. And there is increased production of myeloid derived suppressor cells, which all have a bearing on causing immune paralysis. And it is also shown that these dendritic cells have an important role to play in post-sepsis where there is alteration in this phenotype. And there is reduced cytokine production by these dendritic cells. And there is reduced expression. And I think this has got on with lot of interest. The HLADR, there is reduced expression in the dendritic cells and by the B cells, which are shown to reduce immune failure. And there are 13 studies to look the correlation of HLADR expression and the outermin sepsis, which I'll take you through. So this is a beautiful sort of a graph, which shows this is a study done in 92 patients for a live at Dave Poor, where they measured HLADR. And in the patients where they had a HLADR, good expression of HLADR of more than 8000 in 37 patients, only 10% was the mortality. And if you see this sort of a white graph, where they had 55 patients with a very poor HLADR expression of less than 8000 and they found they had 65% mortality, which means you need to have good HLADR expression by the dendritic cells and by the B cells for patients. It is sort of a prognostic indicator. If you have a good HLADR expression by dendritic cells and B cells, it basically tells you that patients have a better ability to survive. As opposed to the patients where HLADR expression is not happening by these dendritic cells and B cells because of whatever reason. And they have an increased mortality. And there are 13 studies that have been done looking at the HLADR expression. And this is a list of studies where they have shown good relation of HLADR expression and the outcome on the subsist mainly due to immune failure of that type. And HLADR is associated with the immune failure. So now let's look at what are the adaptive immune alteration in subsist. So measurement of HLADR possibly will help us in trying to come out with immune-adjentive therapies. And some of the newer immune-adjentive therapies where energy is being put in these granular site macrophage, polonistimulating factor, interferon gamma. And there are certain good inflammatory cytokines and there are certain anti-inflammatory cytokines which are beneficial. For certain pro-inflammatory cytokines which are being validated or interlept into interferon gamma, IL-17 and CD-28. And some of the anti-inflammatory cytokines which tend to increase in these substances which are bad for the patient and identification of these indicates that the outcome in these patients are bad or interleukin-10. And co-inhibitory receptor of program death protein 1. So this program, cell death protein or PD1 what we call is there is lot of interest enthusiasm or science that is being deliberated on this program death which I will take you through in the next slide. And there is this cytotoxic T lymphocyte antigen 4. So expression of these receptors tell you that these patients are possibly not going to do well because they are more vulnerable for immune failures. And identification of the CD-4 and CD-25 regulatory cells and in fact they have gone the next end of trying to assert on the functional quality of the lymphocytes by measuring the ATP production by these T cells. So the science is advanced to a state where we are trying to see okay there are T lymphocytes in the body but they are not producing enough ATP, it tells us they are fatigue and they are not able to produce antibodies. So this is where we are at at this point of time. But at this point of time we have no gold standard for evaluation of the T cell function. At some of the promising immunotherapy agents where science is working on is the dominant human interluchin 7 and I am telling you more effort or more energy is being put into program cell death 1 protein or anti PD1 antibodies. So this is what we look into. So there are two interluchins where there is lot of research that is going on one is interluchin 7 and interluchin 15. As I said all interluchins are not bad some of the interluchins are very protective and two interluchins which are found to be extremely protective is IL7 and IL15 which I will show in a schematic way. So this IL7 is produced by many cells by stromal cells and thymacells. So this IL7 so basically there is it leads to increased T cell expression. So this IL7 is involved in good T cell expression which is shown to reduce the apoptosis or cell death and what IL7 does is it reduces the expression of this program cell death receptor protein in the T lymphocytes and it activates the T lymphocytes leading to production of interferon gamma which leads to activated macrophages. So one thing listener needs to understand is we need more activated macrophages in these two all the engulfing of toxins and basically this IL7 is one of the variable that leads to mitigation of expression of this program cell death, increased production of interferon gamma and I had produced more activated macrophages. And interluchin 7 is also known to you know show better antigenic expression and there is increase in the integrance that happens due to interluchin 7 which leads to effective transport of these three cells or trafficking of these T cells to the site of the infection. So all in all IL7 is found to be very synergistic in trying to battle this immune failure by activating the macrophages and moving the T cells towards the site of organisms where the present and mitigating the expression of program cell death. So this is what we have understood with IL7 and IL15 is another variable which has shown to be very protective in the species. As you see this IL15 helps in binding of these macrophages to the CD8 cells which are protective and this binding of IL with the CD8 cells and macrophages leads to increase production of interferon gamma which leads to increased cytotoxicity, increased clonal expansion, these differentiation activities. All these are protective elements and IL15 is also known to cause good binding of these macrophages with the NK cells. Again leading to increased burst of interferon gamma and interferon alpha leading to increased proliferation activation cytotoxicity. All in all this whole mechanism leads to reduction in the program cell death or the apopolisis. So the take home at the end of these two slides is IL7 and IL15 are very protective synergistic in reducing the program cell death by increasing the interferon gamma and interferon alpha as we understood. And now so what do we understand by all this pathways. So and granulocyte macrophage, carnage tomorrhaging factor has shown to be a very interesting sort of a therapy targeting at a cellular level. So when you have this activated T cells, B cells or incase cells or macrophage of muscles which typically you want them to be activated in species, they produce granulocyte macrophage polynistimulating factor. And what does this do as the name suggests, it activates the bone marrow and leads to production of these dendrite cells and more macrophages, neutrophils and gocinophils. And these activated T cells also produce GMS GMS CSF which increases the HLADR and we did speak about HLAD. The more expression of HLADR, better it is for the prognosis of the patient. This maturation, survival activation and migration. So GMS CSF is shown to be very beneficial in mitigating this immune failure or immune paralysis. So this is also something that science is working on. Possibly there will be more clinical studies that would be coming looking at whether GMS CSF has a good role in improving the outcome in success. And now I have been talking or sort of articulating about this program cell death one receptor protein. So now they are looking at variables or arsenals to target this PD1 which is anti-program cell death one receptor or protein. So if you see this macrophages do sort of in immune failure, they express this program death ligand one sort of a receptor. And this program death ligand one receptors are also expressed by some of epithelial cells. What this progn, once this macrophages express or your peel lymphocytes or peel lymphocytes express this program cell death. So which means there is immune suppression. So the p cells get exhausted, then you have this IL-10 production and then you have an energy and then the cell death happens and the organ dysfunction happens. Now they are looking at molecules which can target this program cell death and by doing this, it can increase the phagocytosis and increase the production or reduce the production of IL-10 which is not good and it can alter the migration of the macrophages or enhance the migration of those macrophages. So now you have looked at three more. So we have looked at two interlucans which are protective which are IL-5 and IL-15. So IL-7 and IL-15 and we have looked at two targeted sort of molecules that we are looking at which is GMC-SF and anti-PD which possibly will have a beneficial effect in mitigating this immune paralysis. So another aspect that we have understood and which I have been telling is the macrophage gets activated when an individual has a viral or bacterial sepsis and these activated macrophage by itself may not be good enough to mitigate the immune failure. So there are a lot of other sort of a genetic regulation that needs to happen in the macrophage which is to like receptor antagonism, p 38 down regulation and gene transcription regulation and PLR2, collect receptor antagonism. All this can happen with certain immune modulators that have been tried and that leads to TH1 response sort of a enhances the TH1 response and then upwards the cytophenge storm. So basically there are certain tools or immunomodulated agents that are looking at how they could alter the internal milieu of the activated macrophages to have an effective response to the sepsis. So there are pre clinical studies looking at antagonists against the tool like the sub-tour tool. There are agents which are looking at how effectively one can modulate the MAPP. MAPP is the cell signaling modulator. So there are agents trying being looked at which can modulate this cell signaling mechanisms. There are agents being looked at which can alter the genetic profiling of an individual. All in all there are agents being looked at which can reduce the cytophenge storm and lipopolic acurrate is the one which induces fever. There are agents looked at which can cause reversal of this lipopolic acurrate induced fever. All in all the agents which do all of this could possibly help in reducing mortality and many pre clinical studies are being looked at various molecules which can look at all these multimodal effects. So when you look at a sepsis where you have the bugs within the blood vessels, there are different cells. So there is a symphony or orchestra of various cells that come into synchrony to tackle or to fight the sepsis and these are all the cells, CD4, plastic cells, CD8 cells, ejaculate cells, dendritic cells, B cells, etc. So all these have a symphony within themselves and they sort of act in a synergistic way to reduce cell exhaustion, to reduce apoptosis and to reduce cytophenge storm. And this would possibly overcome this regulated adaptive immune response. So this is what we have understood so far about the whole immune mechanism as to why post sepsis immune failure happens. So the summary of my talk is I see a wide immune dysfunction, ease of reality and this happens in the later part of the sepsis and leads to more destructive percent of the, if we put the mortality of sepsis and 40 percent, 10 percent happens in acute phase and we have good agents to reduce the deaths in 10 percent by possibly using particular steroids, early antibiotics, only fluid resistance. But 30 percent of the deaths we tend to happen in the post sepsis is possibly we do not have targeted molecules for that and these are called various types of anti-inflammatory response in room, substance induced immune separation or cellular recovery and we need agents and some of the promising agents that are being looked at is what we saw GMCSF is one and anti-programmed death one receptor protein is something that is being looked at and there are other agents that are being looked at. So we need to really see what really helps and immune monitoring is what we need which can help us in determining the immune identity therapy. When I say immune monitoring, maybe the one which is making inroads is HLA DR expression to see whether which would at least help us prognosticate whether patient is going to get better with all of our interventions and there are a lot of clinical trials happening looking at the immune stratifications as to group the patients which patients do well with certain immune interventions and which patients may not benefit with certain things. But right now we do not have gold standard test for ascertaining the functional test of the immunity like looking at the ATP production of the teal lymphocytes and looking at the fatigue component of the cells. So we do not have a gold standard test. We need robust biomarkers of immune function to determine and prognosticate and look at the interventional tools that may be beneficial to save lives in sub-sufficiency. So thank you all. I would end with this beautiful quote. The following of authorities the denial of intelligence. So thank you one and only. | ↗ |