In the NEWS: Immunotherapy and the Kidney( new data in 2021)- AKI and electrolytes

Immune checkpoint inhibitors (ICI) are a novel class of immunotherapy drugs that have vastly improved cancer care for patients. Data on AKI has been evolving. 

In a multicenter international study just published in JITC by Gupta et al involving 30 sites across 10 countries, researchers collected data on 429 patients with ICI-AKI and 429 control patients who did not develop ICI-AKI. Armed with the largest ICI-AKI database to date, the team of researchers was able to identify predictors, recovery potential and survival outcomes of those patients with ICI-AKI.

One of the most important findings from the two-year study reveals that among patients who take ICI again – even after an episode of ICI-AKI – only 16.5 percent developed recurrent ICI-AKI, which shows that most patients can still take these life-saving medications safely.

Additional findings show that in renal-recovery occurs in approximately two-thirds of patients with ICI-AKI. Early treatment with corticosteroid is associated with a higher likelihood of renal recovery. Lower baseline kidney function, proton pump inhibitor use and extrarenal immune-related adverse events are independent risk factors for developing ICI-AKI.

A related paper recently published in the journal Kidney International by Wanchoo et al looking at the scope of electrolyte disorders that are seen with ICI. Hyponatremia, hypokalemia and hypercalcemia were the most common findings. SIADH is the most common cause of hyponatremia and adrenal disorders led the way in the cause of hypercalcemia. 

In the News: Immune checkpoint inhibitors in the renal transplant patient

 

Use of immunotherapy in the renal transplant patient is challenging. Initial case reports had shown over and over acute rejections. In 2017, we had tried a novel way to prevent rejection in a single case report published in NEJM( using mini steroid pulse and mTOR over CNI use). Since then, we have used this approach successfully in several patients to allow for good tumor response and prevent rejection. But one case, two cases, three cases cannot tell the whole story.  More data is needed. A recent meta-analysis done on use of immunotherapy and transplant patients showed of 44 patients,  18 were reported to have acute rejection. Median time from immune checkpoint inhibitors to acute rejection diagnosis was 24 (interquartile range, 10–60) days. Reported types of acute allograft rejection were cellular rejection (33%), mixed cellular and antibody-mediated rejection (17%), and unspecified type (50%). Fifteen (83%) had allograft failure and 8 (44%) died. Three patients had a partial remission (17%), 1 patient achieved cancer response (6%), and 5 patients had stable disease (28%).

Other studies similar to this have showed similar rejection rates of 40%. No studies have tested the clinical efficacy of the use of these agents in renal transplant patients.

In a recent study published in Kidney International, we collected 69 cases from 23 institutions from US, Canada and Europe. This is the largest study to look at both transplant outcomes and efficacy of these agents in renal transplants patients.

Acute rejection rate 42% (29 out of 69), median ICI to rejection=24 days. Rejection is severe: cellular rejection and mixed cellular and antibody-mediated rejection are both common. Once rejection happened, 65% lost allograft.

What are the risk factors of rejection? Being on 3-agents immunosuppression and mTOR inhibitor use were associated with LOWER risk of rejection. This is an interesting finding. This is to tell us the obvious- the less the immunosuppression- the risk for rejection increases but the mTOR finding is interesting( caution- still low Ns). Take a look at this paper as well.
We looked at rejection rate and cancer objective response rate in skin squamous cell carcinoma (cSCC) and melanoma, two most common cancer types in our cohort. In cSCC, rejection rate 37.5%, ORR 36.4% and ICI may be associated with longer overall survival. In melanoma: rejection rate 54.5% (# of immunosuppression agent-dependent), ORR 40%. OS did not differ but limited by small # of patients and short follow-up.

An important figure that is hidden in the supplemental content is below: This tell us the majority of the changes done by centers when immunotherapy was initiated, see the % who increased steroids, converted CNI to mTOR inhibitors, dc CNI , dc MMF. etc.  Interesting changes which were made are not at all standardized. 

Although our study is to our knowledge the largest multicenter cohort of patients with advanced solid malignancies with kidney transplant who received ICI to date, there are several limitations Firstly it is retrospective and small-sample nature of our cohort limited our ability to adjust for a number of confounders in multivariable analysis for the risk of graft rejection. Also less than half of acute rejection were biopsy proven, which limits the accuracy of the diagnosis of rejection. The comparison of outcomes using these historical cohorts suffers from the lack of power due to the small number of cases, but provides a pragmatic approach to address the risk of rejection and objective response rate. Lastly, immunosuppression modification was the providers’ choice at each institution and not standardized.

So what now? This tells us that immunotherapy is a feasible option for kidney transplant pts but with very high risk of rejection.

mTOR inhibitor plus steroid mini-pulse may be effective in preventing rejection?
Or should we continue the immunosuppressive meds “as is” or at least 2 of them and then give the immunotherapy as efficacy was amazing in cSCC and prevent the rejection as well.
What this study also told us is that- stopping the immunosuppression when planning to give immunotherapy doesn’t really help in cancer outcomes or renal transplant outcomes? So should we be even stopping them??

A collaborative effort led by Naoka Murakami from around the world. 

Topic Discussion: Use of immunotherapy in ESRD patients

Two recent studies from US now describe the use of immunotherapy in ESRD patients. Though both are case studies and series, this is encouraging data.

One study comes from Boston published in AJKD, with a database search leading to 18 patients: overall, six patients (32%) experienced irAEs and two (11%) experienced an irAE of grade 3/4 toxicity (pneumonitis, myocarditis).

Another study from New York published in Kidney 360, with a database search lead to 8 patients: only 2 patients (25%) experienced irAEs overall. A literature review done in that paper also found another 26 patients have previously been described in the literature, with the majority of them from  Italy and China.  Interestingly, 27% of these patients were on dialysis as a result of a rejected kidney transplant due to ICI therapy, and then continued to receive ICI. Over 80% of the patients had either partial or complete response to treatment. Aside from the kidney transplant rejection preceding dialysis, a minimal number of patients had a grade 2, 3, or 4 adverse immunotherapy related event (15%).  In the general population, between 40-60% of patients receiving ICIs experience irAEs at some point during therapy.

Again, due to smaller numbers, we cannot be sure the effects of ICI in ESRD patients but it appears that the rate of irAEs appears similar to general population. 

Concept map: Immune check point inhibitors and the Kidney

This is the summary of the renal effects of ICI therapy on the kidney ( as of Dec 2019). This might change as we learn more and more about these agents.

In the NEWS: PD-1 inhibitors and ATN, not AIN

Check point inhibitors have been associated with kidney injury. The incidence of check point inhibitor associated renal injury varies widely in the literature. The most common kidney biopsy observed has been acute interstitial nephritis and in a few rare cases- podocytopathies. 

In a recent study from France, the authors report on the incidence of pembrolizumab associated kidney toxicity in a French single-center nephrology referral center and report that renal adverse events occur in 1.77% of patients. A renal biopsy was performed in all 12 patients and acute tubular injury was the most common lesion noted. The most common glomerular pathology in this case series was minimal change disease. In this study, surprisingly, acute tubular injury was the most commonly observed pattern of injury on histology. This is in contrast with other reports that identified acute tubulo-interstitial nephritis as the dominant form of renal injury associated with immunotherapy treatment. A possible explanation is the low threshold to perform a kidney biopsy in this study. 

About half of their patients had ATN. Those patients had more frequently cardiovascular risk factors and marked histological vascular lesions and are more frequently men than AIN patients. Two of them received platinum but at least 1 year before pembrolizumab was introduced. No known mechanism is postulated for the ATN related to pembrolizumab.

This is an important study as this highlights the varied degree of renal toxicities seen with these agents. AIN will respond to steroids and ATN won’t. A kidney biopsy will be important to distinguish that. Empiric steroid treatment by oncologist should not be the gold standard but should be based on kidney biopsies performed and or a nephrology consultation. 

Besides AIN and podocytopathies, it appears that PD-1 inhibitors also can cause ATN.

Topic Discussion: CAR-T therapy and the Kidney

A new dawn is breaking in the field of hematologic malignancies, as the first product based on chimeric antigen receptor (CAR) T cells was scrutinized today by a panel of experts and unanimously recommended for approval at the FDA for pediatric and young adult patients (age 3-25 years) with relapsed or refractory acute lymphoblastic leukemia (ALL).

Blood is collected from the patient, and then autologous T cells are separated out and genetically engineered. The process involves inserting a CAR that targets CD19, an antigen expressed on B cells and tumors derived from B cells.  These CAR T cells are then infused back into the patient, who has undergone chemotherapy, and in the body the product homes in on B-cell leukemic cells and destroys them.  The main action happens mostly about 2 weeks after those CAR-T cells have been re-infused.  Some have termed this form of therapy as the “ living drug”

Autologous CAR-T cell therapy first shot into headlines about 4-5 years ago when it was thought about in CLL patients.   Then several other studies were done essentially confirming that the concept is correct but there are serious toxicities.

https://www.ncbi.nlm.nih.gov/pubmed/25317870 (leukemias)

https://www.ncbi.nlm.nih.gov/pubmed/26760100 (myelomas)

https://www.ncbi.nlm.nih.gov/pubmed/28029927 ( gliobastoma)

The technology is complicated and initially when tried in CLL led to multiple toxicities of various organs including CNS, cardiac, renal and mostly requiring ICU admissions from acute cytokine release syndrome. This happens due to high levels of IL-6, a cytokine that is secreted by T cells and macrophages in response to inflammation.  Etanercept and tocilizumab have been used to block the IL-6 activity to treat such side effects.

Acute renal injury following CAR T-cell infusion is multifactorial and almost always reversible. Reduced renal perfusion is often the most important cause of renal injury. Reduced renal perfusion can be caused by cytokine-mediated vasodilation, decreased cardiac output, or intravascular dehydration due to insensible losses from high fevers. Tumor lysis syndrome and drug effect from medications such as antibiotics are other possible causes of renal injury. Electrolyte disturbances, such as hyponatremia, hypokalemia, and hypophosphatemia are not uncommon but have been reported. A recent article in Blood summarizes all toxicities.

Now the therapy has returned and we may see this in many centers. We must be aware of the cytokine release storm that it can cause leading to AKI in that setting.  There might be more in the pipeline of similar products such as the one that just got approved for ALL.

Figure source: http://www.lymphomation.org/programing-t-cells.htm

IN THE NEWS: Preventing rejection while using immunotherapy in organ transplants

Use of immunotherapy such as CTLA-4 and PD-1 inhibitors have been sparingly used in renal transplant patients due to the concern for rejection.  Several cases and one recently published in NEJM last year showed severe acute cellular and antibody mediated rejection with use of PD-1 inhibitor therapy. In the limited number of patients who have received these agents, it appears that PD-1 inhibitors could be more prone than CTLA-4 antagonists to cause rejection in the transplanted kidney. This is especially true when the patients receive anti–CTLA-4 agents before PD-1 inhibitor treatment. 

We reported now in NEJM a creative solution of preventing rejection in a patient getting nivolumab (PD-1 inhibitor). By using a prophylactic approach of higher doses of steroids and mTOR inhibitors, we were able to successfully prevent rejection along with successful treatment of the cancer as noted in the supplementary files of the letter. Immune check point inhibitors have revolutionized the treatment of many types of cancers.With this approach, it is possible that these agents can be perhaps safely be used in the organ transplant patient.

We recently reviewed entire literature on the use of immunotherapy in the organ transplant world. As stated above, the rejections were mostly seen in PD-1 inhibitor based therapy compared to CTLA-4 therapy. In addition, the 2 cases of liver transplant where these agent were used and 1 case of heart transplant didn’t lead to a rejection episode.  But in the renal transplant patients, 5 cases have now been reported of leading to acute cellular and antibody mediated rejection when PD-1 inhibitor was administered. The above NEJM case suggests a potential treatment strategy.

Renal effects of immunotherapy are not minor.  AIN, podocytopathy and electrolyte disorders have been reported. It is important for the general nephrologists to know about these effects.Two recent reviews discuss this elegantly.

http://www.karger.com/Article/FullText/455014
http://ndt.oxfordjournals.org/content/early/2016/12/23/ndt.gfw382.abstract

Immunosuppresion Medications in Nephrology

Since the 1970s, the transplant literature has been soaring with anti rejection medications. In the last decade, we as nephrologists are starting to learn from Rheumatology and Oncology on novel targets to treat GNs and Rejections in grafts. A recent review in CJASN highlights the different categories of agents in immunosuppression that we have to our disposal.

T cell directed therapy that target signal 1 from TCR and antigen presenting cell such as OKT3 and  and CNIs
T cell directed therapy that target signal 2 that is costimulatory such as Abatecept and belatacept. In addition, there are newer agents being developed for co situmatory blockade by CD154;CD40 targeting.

B cell directed therapy such as Anti CD20 agents such as rituximab, ocrelizumab and veltuzumab
B cell directed therapy such as Anti CD22 agents such as epratuzumab being tried in SLE
B cell targeting agents for B cell differentiation such as belimumab and atacicept.
Plasma cell targeting agents such as bortezomib( carfilzomib hasn't entered the renal world yet)

Complement inhibitors such as eculizumab
Cytokine targeting agents such as steroids
Specific cytokine agents such as anti IL-2 antagonist( basiliximab) and anti TNF alpha
IL-1 antagonists such as anikinra and canakinumab
IL-6 inhibition by tocilizumab being studied in transplant patients
IL-17 inhibition by secukinumab not currently being utilized in renal patients

mTOR inhibitor such as sirolimus and everolimus
Anti CD52 such as campath and alemtuzumab
Inhibition of DNA synthesis by azathioprine, mycophenolate, and leflunomide
Cytotoxic agents such as cyclophosphamide used for many GNs
Finally, pooled polyclonal abs such as IVIG have been used and polyclonal antithymocyte globulins for induction.

Topic Discussion: Do B regulatory cells exist and do they help in transplant tolerance?

Recently, David Rothstein from Pittsburg gave an amazing grand rounds on B regulatory cells in NYSN in New York. Here are some notes on what I learnt.

B cells can influence T cell differentiation but B cells are effector cells themselves.  B cells also are responsible for antibody production. Do B regulatory cells exist?

Koichi et al showed in an elegant manner that certain subset of B cells in mice produce IL-10 and they might have regulatory function. In addition, IL-10 production was restricted to this CD1d^hiCD5⁺ B cell subset, with IL-10 production diminished in Cd19^−/− mice. Thereby, CD1d^hiCD5⁺ B cells represent a unique subset of potent regulatory B cells per authors in that study.

Ding et al in JCI showed that B cells that had the IL-10 production also had a TIM-1 marker.  What is TIM-1.  T cell Ig domain and mucin domain protein 1 (TIM-1) is a costimulatory molecule that regulates immune responses by modulating CD4⁺ T cell effector differentiation. TIM-1 was expressed by a large majority of IL-10–expressing regulatory B cells in all major B cell subpopulations, including transitional, marginal zone, and follicular B cells, as well as the B cell population characterized as CD1d^hiCD5⁺.  They showed that with a  low-affinity TIM-1–specific antibody that normally promotes tolerance in mice, actually accelerated (T cell–mediated) immune responsiveness in the absence of B cells. TIM-1⁺ B cells that had IL-10 expression  could directly transfer allograft tolerance.  What is possible is that TIM-1 is an inclusive marker for IL-10⁺ Bregs.

Could these be the cells that induce tolerance in transplant patients?

Yeung et al answered this question in mice. B cells that express a mutant form of TIM-1 lacking the mucin domain (TIM-1^Δmucin) are unable to produce IL-10 in response to specific ligation with anti-TIM-1. TIM-1^Δmucin mice also exhibit accelerated allograft rejection, which appears to be due in part to their defect in both  baseline and induced IL-10⁺ Bregs, since a single transfer of WT TIM-1⁺ B cells can restore long-term graft survival.

That’s in mice studies. It is impossible to measure TIM-1 in humans as percentage of these cells might be just <1%.

To make things more exciting, there might even exist a subset of regulatory plasma cells that produce IL-35. So is IL-35 producing cells also a type of B regulatory cells.

No one is aware of a disease entity that exists that is a Breg deficiency. IPEX syndrome is a Treg deficiency syndrome. One study has looked at kidney transplant human samples in JASN and using Breg data. 

Cherukuri etal. examined the cytokine profiles of human samples and found that subsets of CD24(hi)CD38(hi) transitional B cells (TrBs), CD24(hi)CD27(+) memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-α simultaneously. TrBs had the highest IL-10/TNF-α ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. What was important was the  ratio of IL-10/TNF-α expression, a measure of cytokine polarization, as an indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-α expression (i.e., reduced IL-10/TNF-α ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-α ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. So, B cell-mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.  This is an amazing start. Hope to see more of this work to help us figure out the holy grail of transplant- tolerance!!

Interestingly, in a study done in NEJM where rituximab was used to deplete B cells as induction agent in transplantation, there were more rejection episodes in that arm.  Perhaps there was too much B reg depletion?   

In the News: LG3 and the Transplanted kidney

Antibodies have always been the biggest concern in transplantation. During vascular rejection, there is endothelial cell damage. The apoptotic endothelial cells release a fragment of perlecan referred as LG3.  

A recent study in the AJT identified a novel antibody that may be playing a role in vascular form of antibody mediated rejection. The authors call this anti-LG3, an antibody that some patients produce to attack a protein that plays an important role in vascular repair and regeneration, LG3. In these patients, the secretion of LG3 by the new kidney stimulates the activity of these antibodies which attack and injure the blood vessels of the transplanted organ, and the normal healing process of the transplanted organ is impaired. Patients who experienced vascular rejection had elevated anti-LG3 titers pre and posttransplantation compared to subjects with interstitial form of rejection( cellular) or stable graft function significantly respectively.  The authors also confirmed these findings with mice data. Collectively, these data identify anti-LG3 antibodies as novel accelerators of immune-mediated vascular injury and obliterative remodeling. One prior animal study showed similar findings. 

Do we have a new marker for potential vascular rejection? What is the data on LG3 in other forms of endothelial injury namely CNI induced TMA or other forms of endothelial damage? Then again, the perlecans are altered in certain genetic diseases that don't quite fit the role they play in transplantation. 

TRANSPLANT ROUNDS: Test your knowledge of induction agents!

To test your knowledge of induction agents in kidney transplantation, we invite you to complete the following matching quiz. The answers will be posted early next week.

Match the following induction agents with the description that best matches their profile. One description will not be used.

Alemtuzumab	A. This anti CD25 human/ mouse chimeric antibody is almost devoid of side effects. It does not increase the risk for malignancies or infections.
Rituximab	B. This antibody has been used in a recent trial to facilitate positive crossmatch transplantation in living donors by blocking the effector pathway of antibody mediated allograft injury.
Thymoglobulin	C. This agent is used to treat antibody mediated rejection and as induction in sensitized individuals. It decreased the production of anti-HLA antibodies by targeting the CD 20 receptor on B cells and plasma cells.
Daclizumab	D. This antibody targets CD 52. It is FDA approved for the treatment of CLL. It is often used in minimization protocols for kidney transplantation.
Basiliximab	E. This agent when used as an induction agent may increase the risk of cellular rejection.
Atgam	F. This polyclonal antibody preparation targets many different receptors on T cells. It increases the risk of PTLD, and CMV compared to no induction or anti-CD25 induction. However, it has been shown to be a superior agent in reducing rejection episodes and prolonging graft survival especially in high risk individuals.
OK3T	G. This polyclonal antibody preparation came from horses. It has since been largely replaced by another polyclonal T cell preparation.
Eculizumab	H. This agent was a humanized monoclonal antibody that targeted the alpha chain of the IL-2 receptor of T-cells. The manufacturer discontinued its use in January 2009.
	I. This monoclonal antibody against the T-cell receptor was the first such antibody used for any clinical indication in the United States. Its current use has been minimized due to severe adverse reactions including serum sickness and pulmonary edema.

Answers soon to follow! Stay tuned.

In the News: Inducible Apoptosis- but could it work in a solid organ transplant model?

Immunology is evolving rapidly in the medical field. A recent article of mention is the NEJM Nov 2011 issue that talks about the inducible apoptosis as a safety switch for adoptive cell therapy.

This article is more of a cancer paper that discusses an inducible T cell safety switch that was based on the fusion of human caspase 9 to a modified human FK-binding protein - allowing for dimerization.  Eventually, when exposed to a synthetic dimerizing drug, caspase 9 was induced and activated leading to cell death.  So, they tested this hypothesis using the stem cell transplant model and GVHD treatment. Five patients who had undergone stem-cell transplantation were treated with the genetically modified T cells.  A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence.

Interesting, look back at the literature on icasp9, this was tested apparently in erythropoietin transgene expression in animals. The effectiveness of the caspase-9-based artificial "death switch" as a safety measure for gene therapy based on the erythropoietin (Epo) hormone was tested in vitro and in vivo using the chemical inducer of dimerization. They concluded that inducible caspase 9 did not interfere with gene transfer, gene expression or tetracycline control and may be used as a safety mechanism for gene therapy. 

This iCasp9 cell suicide system is interesting and perhaps might have role in Renal transplantation. It seems that prior hematology literature have demonstrated the feasibility of engineering allogeneic T cells with two distinct safety mechanisms, selective allodepletion and suicide gene-modification. Could these suicides genes be selectively allowed to target reactive T cells in organ transplants and let the T regs flourish? Unclear data on that.  Unclear how successful it would be in a solid organ transplant model. Any thoughts?

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/22047558

http://www.ncbi.nlm.nih.gov/pubmed/20499015

CONSULT ROUNDS: Normal Complements and Infection associated GN

Post infectious GN usually has been associated with hypocomplementemia.  There are certain situations where the complements can be normal and you still have an "infection" associated GN.
A nice trail by history revealed an old article from 1970s from NEJM. They studied 11 patients with visceral abscesses in whom renal injury was present. All biopsies showed diffuse proliferative GN.  7/11 had normal complements and 4/11 had low complements. No endocarditis was present and no cryoglobulins. The course of the renal disease closely related to the resolution of the abscesses. Hence this is a very important cause of normal complement associated post infectious or "infection associated immune complex disease"

To take this topic further. It is not uncommon to see normal complements in early classic post infectious GN. Clinical suspicion and history can sometimes be more important than lab tests. Take a look at the second article listed below which is also from 1970s regarding early complements levels in PIGN.

A new entity called Post infectious Ig A variant of PIGN can also lead to normal complements and similar picture. In this case, one sees mesangial deposits of IgA in a PIGN setting with neutrophils; usually in DMII, elderly and Staph infections.  Check out an NDT article below regarding this entity.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/1272347
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1607211/
http://ndtplus.oxfordjournals.org/content/4/3/181.short?rss=1

Topic Discussion: TIM molecules and Kidney Transplantation

TIM is "T cell immunoglobulin mucin". They are molecules that have shown to play a major role in immune responses. TIM 1,3 and 4 are the ones mainly noted in the literature.  TIM-1 and 3 are more on T cells and Tim-4 on Antigen presenting cells.

TIM 1:- Expression is on CD4+T cells, B cells, Mast cells and NK cells.  The proposed ligands for this molecule are TIM-4, IM3, and IgA and heavy chain to name a few.  The role in innate immunity is mediating clearance of apoptotic bodies and maintenance of peripheral tolerance.  In adaptive immunity, it increased th2 differentiation. Disease models include increased expression Asthma, MS, Sarcoidosis, and epithelial cells in AKI( also called KIM-1)

TIM3:- Expression on TH1 and Th17 cells, CD8+T cells and Antigen presenting cells.  Innate immunity wise limits macrophage expansion and modulates CD80 and CTLA-4 expression on antigen presenting cells.  It also helps in peripheral tolerance.  Disease models include T cells in chronic malignancy and infection.  Down regulated in Asthma and MS

TIM4:- Expression on dendritic cells and macrophages.  Ligands are TIM 1 and CD4+ t cells.  It up regulates Th2 responses and proliferation of activated T cells.  Disease model is food allergies and Asthma.

The TIM family is appearing as modulators of the immune system and helps in co stimulation of T cells. More will come about these molecules to improve our understanding of transplant immunology.


ref:
http://www.ncbi.nlm.nih.gov/pubmed/17331850
http://www.ncbi.nlm.nih.gov/pubmed/21906254
http://www.ncbi.nlm.nih.gov/pubmed/20536563
http://www.ncbi.nlm.nih.gov/pubmed/16938542

IN THE News: A report about inducing tolerance in kidney transplants

A nice letter from investigators at Stanford published this week in NEJM Oct 2011 issue shows a proof of concept. 12 patients, got a HLA matched kidney and a donor cell infusion of CD34+ progenitor cells mixed with CD3+ T cells and irridiation and anti thymoglobuliun. The irridiation was not total body but more to spleen, thymus and lymph nodes. Giving stem cell transplantation and kidney transplant to a well matched patient led to chimerism and ultimately majority patients came off immunosuppresion and renal function is stable. Take a look at the full letter at

http://www.nejm.org/doi/full/10.1056/NEJMc1107841

In the News:- TOLL like receptors and Nobel Prize in Medicine 2011

The nobel prize this year in 2011 for Medicine is going to the discovery of the Toll like receptors and dendritic cells. Check out the website of Nobel Prize at : http://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/#
Some minor information.


Dendritic cell:- An antigen presenting cell is a very prominent cell now in our textbooks and especially when we deal with transplantation immunology. This was discovered by Ralph Steinman in 1973. He speculated that it could be important in the immune system and went on to test whether dendritic cells could activate T cells, a cell type that has a key role in adaptive immunity and develops an immunologic memory against many different substances. 
Toll like receptors: Bruce Beutler was searching for a receptor that could bind the bacterial product, lipopolysaccharide (LPS), which can cause septic shock, a life threatening condition that involves overstimulation of the immune system.  TLR were hence discovered. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes. They are more like pattern recognizing receptors. Three subgroups of TIR domains exist. Sub group 1 are receptors for interleukins, subgroup 2 directly to microbes, subgroup 3 to get signals from subgroup 1 and 2. 

image Source: Wikipedia.com

IN the NEWS:- TIM-1 + B cells? and B cell tolerance!

TIM-1 is a costimulatory molecule that regulates immune responses by modulating CD4⁺ T cell effector differentiation. A recent mice study in JCI showed that it is expressed mainly in B cell subpopulation.  And these TIM-1 positive cells that are B cells also produced IL-10. IL-10 is a very important regulatory molecule like Foxp3.  These B cells were  characterized as CD1d^hiCD5⁺. Some consider these as B cells that have regulatory function.  TIM-1⁺ B cells were highly enriched for IL-4 and IL-10 expression, promoted Th2 responses, and could directly transfer allograft tolerance. Prior studies have shown such cells in mice to help keep SLE quiet and inflammation under control. Perhaps, just like the T regs, there is a small but strong population that are present called B reg cells. Now studies so far have only found these in mice. Can this hold true in human studies is hard to tell yet. Perhaps! It will be important in the field of transplantation to sought this out as we move forward towards a better world of transplant tolerance. Why do some people have more tolerance than other? Perhaps its a Breg phenomenon.  The current study suggests that TIM-1 may be a novel therapeutic target for modulating the immune response and provide insight into the signals involved in the generation and induction of Bregs.


Check it out
http://www.ncbi.nlm.nih.gov/pubmed/21821911

IN THE NEWS: Rituximab Targeting Podocytes in Recurrent FSGS

Rituximab might be working in a non B cell mediated manner in FSGS recurrence post transplant.
A new study by Fornoni et al showed this in an elegant way.
Some summary points

1. 41 patients were studied, post transplant and 14 were controls and remaining received rituxian as part of their induction.
2. Fewer podocytes with SMPDL-3b protein in biopsies from recurrent FSGS were found.
3. Serum from patients with recurrent FSGS had a decrease in both SMPDL -3b and sphingomyelinase activity.
4 They predicated that rituximab preserves SMPDL-3b expression in podocytes.
5.The above part was prevented with anti CD20 treatment.
6. They studied SMPDL-3b protein, cytoskeleton remodeling in cultured normal human podocytes that had been exposed to patient sera with or without rituximab.
7. Over-expression of SMPDL-3b or treatment with Anti CD20 was able to prevent recurrent FSGS and showed preservation of cytoskeleton.
8.These data suggest that modulation of the sphigolipid related proteins might be playing a role in causing recurrent FSGS and perhaps anti CD20 agents are inhibiting this process in a B cell independent fashion.

Key: SMPDL= sphingomyelin phosphdiesterase acid like.

ref:
http://www.ncbi.nlm.nih.gov/pubmed/21632984

T regulatory Cells: A short review

T regulatory cells have now come out and made a splash in the transplant world but also in the immunology and glomerular disease world.  Treg are usually CD4+, CD25+, CTLA4+.
A common misconception is that all are Foxp3 positive.  

There are many types of Tregs.

Natural kind that do express Foxp3 and CD25 and they usually are IL-2 dependent

Induced Tregs are induced in the periphery and can express Foxp3 but after development

Regulatory Tregs do not express Foxp3 and CD25. They depend on IL-10 on development.

IL-10 has always been associated with regulatory function.

Now given above information, immunology always is evolving and who knows what will be new in 2011.

TOPIC DISCUSSION: Dendritic Cells and Renal disease

Dendritic cells(DC) are traditional thought to be anti infectious and a link between the innate and the adaptive immune system.  A nice breakdown of DC role in kidney disease recently discusses its role in homeostatic, anti inflammatory and pro inflammatory roles in kidney diseases.
In terms of homeostatic roles: there is evidence that DCs can do some immune tolerance in renal allografts, and small molecular weight antigens.  The anti inflammatory roles have been in mostly nephrotoxic nephritis(drug induced) especially cisplatin nephrotoxicity. Some data is also present in suppressing pro inflammatory cytokines in ischemic reperfusion injury. Most of the data is in being pro inflammatory in nature and that is in causing proteinuria, promoting ANCA through Th cells, IL-12 secretion in lupus and Th1 response in tubular insterstitial disease.
This leads us to believe that there might be many types of DC and there are.  CD11B like DC due immune surveillance and activate Th cells and are present in kidney in certain glomerular diseases.  CD8 like DC are found in renal lymph nodes and have some T cell activation role.  Inflammatory DC regulate Th cells and Plasmacytoid DC may have some role in lupus nephritis.

Check out these recent references.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21613986
http://www.ncbi.nlm.nih.gov/pubmed/19276627
http://www.ncbi.nlm.nih.gov/pubmed/19381017