Answer to Immunology Quiz 2

Immunology Quiz 2:
Which of the following drug & target of action combinations incorrectly matched?

Responses:
Tacrolimus/Calcineurin - 16%
Basiliximab/CD3 - 66%
MMF/IMPDH - 8%
Sirolimus/mTOR - 16%
Belatacept/CD80,86 - 33%
Compath/CD52 - 8%
OKT3/CD25 - 66%

Answer:
As majority of you indicated, the incorrect combinations are Basiliximab/CD3 and OKT3/CD25. Basiliximab acts by blocking IL2 receptor, also known as CD25. OKT3 or Muromonab-CD3 is a monoclonal antibody to CD3 on T cells. 33% of you marked Belatacept/CD80,86 as incorrect combination. However, this is a wrong choice as CD80/86 on antigen presenting cells is indeed the target of action for Belatacept there by inhibiting CD28 costimulation pathway of T cell activation.

Rituximab for induction?

A trial from Sweden was published last year in Transplantation.  It was a prospective, double blind, randomized, placebo-controlled multicenter study on the efficacy and safety of rituximab as induction therapy, together with tacrolimus, mycophenolate mofetil, and steroids in kidney transplants. The primary endpoint was defined as acute rejection, graft loss, or death during the first 6 months. They randomized 140 patients and found no difference in rejection episodes, infection episodes.  There was a tendency toward fewer and milder rejections during the first 6 months in the rituximab group. A commentary of this also got published in recent May issue of Transplantation.
More trials need to be done with this agent before we think it can be used as an induction agent. Trails of using it as an induction in lupus also have been done in Europe with promising results.
Other areas where it is being used in highly sensitized individuals to desensitize. In cases of historical cross matches that are positive. Rituximab is becoming standard drug to give patients with antibody mediated rejection.

Panel Reactive Antibody? how do you calculate?

We always talk about the PRA is 0% and 50% and so forth. How is that calculated?
Well, there is a calculator. The CPRA estimates the percentage of donors that would be incompatible with the candidate, based on the candidate's unacceptable antigens.
Check out http://www.unos.org/resources/frm_cpra_calculator.asp


When you go to the calculator, you enter all the unacceptable antigens for the patient and it spits out a value. 

This has been validated by OPTN/UNOS Histocompatibility subcommittee. Then based on the center, the decision is made.  This algorithm is a more accurate measure of sensitization because it accounts for both Class I and II antigens

You can learn more about it at the UNOS website

Are you aware of MICA antibodies?

Some kidney transplants fail despite good HLA matches. The main targets for antibody mediated rejection are HLA antigens. Among non-HLA antigens that can induce an antibody response, MHC class 1-related chain A (MICA) antigens appear significant enough to affect acute and chronic graft outcomes. MICA antigens are expressed on endothelial cells, dendritic cells, fibroblasts, epithelial cells but not on peripheral blood lymphocytes. As they are expressed on endothelial cells, it seems that antibodies against MICA antigens are harmful especially to vascularized allografts like renal allograft. In a landmark study (Zou et al, NEJM Sep 2007), pretransplantation MICA antibodies were found in about 11% of 1910 renal transplant recipients. It was found that recipients with pre-transplantation MICA antibodes had lower 1-year graft survival compared to those without MICA antibodies suggesting adverse role of these antibodies. However, a more recent but smaller study (Lemy et al, Transplantation, May 2010) failed to replicate same findings. In this study, MICA antibodies did not adverse affect renal allograft outcomes.

Immunology Quiz 1 Answers

Immunology Quiz Corner: Which one is Matched INCORRECTLY? Th1 and IL-12   0 (0%) Treg and IL-6   3 (50%)   Th2 and IL-4   1 (16%)   Th17 and IL-6   2 (33%)
The correct answer is Treg and IL-6.  After the encounter with an antigen and co stim molecules presented by antigen presenting cells, the naive T cells that is CD4+ can differentiate into different type of T cells.  The commitment to which T cell type it becomes depends on the cytokine that is pre dominant.  In the presence of Interferon Gamma and IL-12, Th1 cells predominate that are responsible for intracellular bacteria and cell mediated immunity.  In the presence of IL-4, Th2 dominate that are predominately for allergic diseases.  In the presence of IL-6 and IL-23 in the presence of TGF-B, Th17 dominate , they are responsible for extracellular bacteria and fungi and cell mediated autoimmunity.  Finally, in the presence of TGF-B and retinoic acid, FoxP3 positive T regs dominate that are regulatory in nature. There might be more regulatory T cells around in the immune system that we still haven't discovered.
A nice review of this in the context of TH17 immune response was recently published in Kidney International
http://www.ncbi.nlm.nih.gov/pubmed/20375986

Rituximab induced lung injury

Rituximab is being used for many kidney diseases and now in the post transplant world as well
A recent report in pediatric Nephrology journal discusses a pulmonary complication of the drug.
This first report of rituximab-associated, Cryptogenic Organising Pneumonia  highlights the risk of pulmonary complications after treatment with B-cell depleting agents in solid organ transplant recipients.

http://www.ncbi.nlm.nih.gov/pubmed/20140460
http://www.ncbi.nlm.nih.gov/pubmed/19681063
https://www.pediatric-nephrology.com/daily-updates/2010/05/31/212-ralimore.html

B cell signature and Tolerance

Recently we discussed B regulatory cells. Before one could think, a study in JCI discusses this very topic of B cell signature in tolerant renal transplant recipients.  This is the largest cohort of tolerant renal patients and when they did compared gene expression profiles, they found that the predominant Cell was a B cell that was regulating the maturing of most B cells. IL -10 was also significant.  This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. 
Finally, B cells are making a mark, just lagging slightly behind the T cells.
Hmmm. is Rituximab all good then???


Reference
http://www.ncbi.nlm.nih.gov/pubmed/20501946
http://www.ncbi.nlm.nih.gov/pubmed/20501943

Nephrology World on Intragraft gene expression

http://nephrologyworld.blogspot.com/2010/06/intragraft-gene-expression-can-predict.html

Kidney Transplant as an Outpatient Procedure

This ATC 2010, North Shore/LIJ Center of Kidney Transplantation presented an abstract about a 48 hour discharge kidney transplant program. A nice editorial on this can be seen in the most recent ASN Kidney News.  Selected patients with the right multi-team approach along with Nephrologists, Social workers and coordinators, this is very possible.
The re admission rate was low, complications were low along with a cost effective strategy.

Check it out at ASN Kidney News online version.

Journal Club: B regulatory cells

Today at Immunology Journal Club, we discussed an article from PNAS. It was a discussion of how Apoptotic cells in the setting of BALB/C, NOD and CIA mice models, showed increased CD4+ T cell production producing IL-10 via a B regulatory cell crosstalk also producing IL-10.
This is a fascinating paper and adds to the ongoing papers on B regulatory cells. We know a lot about T regs and its relation to Foxp3 and being the "policemen" cells and causing negative regulation of immunity. B cells were classically thought of as effector cells and now there is emerging data in the last decade that there might be some role of B cells in regulation as well in Encephalitis models, Diabetes, Collagen induced arthritis and latest off the press also in murine lupus models.
This might implications once we see some human data, so far none in nephrology and transplantation, oncology and rheumatology.
Here are some very good references:
http://www.ncbi.nlm.nih.gov/pubmed/20368280
http://www.ncbi.nlm.nih.gov/pubmed/20368271
http://www.ncbi.nlm.nih.gov/pubmed/18759928
http://www.ncbi.nlm.nih.gov/pubmed/20146707