antibody barriers1

8/14/2019 antibody barriers1

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Overcoming antibodiesOvercoming antibodiesbarriers in renal transplantbarriers in renal transplant

Hanan FathyHanan FathyAssistant lecturerAssistant lecturer

Pediatric Nephrology DepartmentPediatric Nephrology DepartmentAlexandria UniversityAlexandria University


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a The shortage of donor organs, especially inThe shortage of donor organs, especially in

renal transplantation, leads to an increasingrenal transplantation, leads to an increasing

discrepancy between the number of end-stagediscrepancy between the number of end-stage

renal disease patients on waiting lists and therenal disease patients on waiting lists and the

number of available deceased donor kidneys.number of available deceased donor kidneys.

a Expansion of the donor pool can be achieved byExpansion of the donor pool can be achieved by

increasing the numbers of living kidneyincreasing the numbers of living kidney

transplantation and by overcoming thetransplantation and by overcoming the

immunological barriers of ABO-incompatibilityimmunological barriers of ABO-incompatibility

and HLA-sensitization.and HLA-sensitization.


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HISTORYHISTORY

Attempts to overcome barriers to kidney transplantsAttempts to overcome barriers to kidney transplantsare not new. In the 1980s some patients wereare not new. In the 1980s some patients weresuccessfully transplanted following plasmapheresis,successfully transplanted following plasmapheresis,

But it was not embraced by the transplantBut it was not embraced by the transplantcommunity because it was expensive.community because it was expensive.

In Japan, however, where deceased donor kidneyIn Japan, however, where deceased donor kidneytransplantation is unpopular, scientists saw thetransplantation is unpopular, scientists saw theprocedure as the only way to save many lives.procedure as the only way to save many lives.

In 1998, they surprised the transplant communityIn 1998, they surprised the transplant communitywhen they reported an eight-year follow-up study onwhen they reported an eight-year follow-up study on61 patients who had had ABO incompatible61 patients who had had ABO incompatibletransplantstransplants


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How are anti bodies producedHow are anti bodies produced

a Plasma cells make up an important part ofPlasma cells make up an important part of

your immune system.your immune system.

a They are mature B lymphocytes (white bloodThey are mature B lymphocytes (white bloodcells), often referred to as B cells. They arecells), often referred to as B cells. They are

produced and mature in the bone marrow andproduced and mature in the bone marrow and

concentrate in the spleen and lymph nodes.concentrate in the spleen and lymph nodes.

a

They produce millions of types of B cellsThey produce millions of types of B cellsevery day. Each type has a unique receptorevery day. Each type has a unique receptor

protein, called the B cell receptor (BCR) on itsprotein, called the B cell receptor (BCR) on its

membrane that is designed to fit one specificmembrane that is designed to fit one specific

antigen.antigen.


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How are anti bodies producedHow are anti bodies produced

aWhen an antigen combines with a B cells antigenreceptors and is stimulated by T cell secretions calledcytokines, the B cell undergoes clonal expansion.

a The result is many plasma cells, which producespecific antibodies against this antigen along withmemory B cells.

a After the infection, or exposure passes, plasma cells

undergo apoptosis.

aMemory B cells, which keep the ability to recognizethis antigen, are retained in the body.


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Antibody Production FactoriesAntibody Production Factories

Antibodies at work


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a ABO incompatibility or a positive crossmatch due toABO incompatibility or a positive crossmatch due toanti-HLA (Human Leukocyte Antigen) antibodies wasanti-HLA (Human Leukocyte Antigen) antibodies wasonce an absolute roadblock to kidney transplantation.once an absolute roadblock to kidney transplantation.

a Most of patients die while waiting for a negative cross-Most of patients die while waiting for a negative cross-match deceased donor kidney, yet most of them wouldmatch deceased donor kidney, yet most of them wouldbe candidates for living donor kidney transplantation ifbe candidates for living donor kidney transplantation ifwe could overcome the destructive effect ofwe could overcome the destructive effect ofantibodies.antibodies.

a In addition, these procedures are cost-effective whenIn addition, these procedures are cost-effective whencompared to maintenance dialysis therapy.compared to maintenance dialysis therapy.

Antibody barriers to kidneyAntibody barriers to kidneytransplanttransplant


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a As blood group antigens are expressed by theAs blood group antigens are expressed by the

endothelium of solid organs including the kidney,endothelium of solid organs including the kidney,

transplantation across the blood group barrier can resulttransplantation across the blood group barrier can result

in hyperacute antibody-mediated allograft rejection.in hyperacute antibody-mediated allograft rejection.a ABOABO--incompatible transplantation was already performedincompatible transplantation was already performed

as early as in the 1970s, but due to hyperacute rejection,as early as in the 1970s, but due to hyperacute rejection,

results were discouraging.results were discouraging.

a Due to a severe shortage of available deceased donorDue to a severe shortage of available deceased donor

organs, most ABO-incompatible kidney transplantationsorgans, most ABO-incompatible kidney transplantationshave taken place in Japan.have taken place in Japan.


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The Johns Hopkins protocol:The Johns Hopkins protocol:Four to five pre-operative

plasmapheresis sessions to removeanti-A/B antibodies.

Each session followed by theadministration of cytomegalovirus

hyperimmune globulin.

After achieving a pre-transplant

A/B-antibody titre of


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The Johns Hopkins protocol (cont):The Johns Hopkins protocol (cont):

Immunosuppression with tacrolimusand mycophenolate mofetil wasinitiated, followed by steroids anddaclizumab after transplantation

Post-operative treatment includedanother three plasmapheresis/CMVIg

sessions on days 1, 3 and day 5.


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The immunosuppressive regimen consisted of:The immunosuppressive regimen consisted of:Specific anti-A or anti-Bimmunoadsorption columns (Glycosorb)are currently avaliable. Four pre-operative immunoadsorptionsessions were performed, aiming for apre-operative ABO antibody titre of


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One dose of rituximab (375 mg/m2)given 24 weeks beforeimmunoadsorption.

Followed by a conventional triple-drugImmunosuppression consisting oftacrolimus, mycophenolate mofetil andprednisolone, starting 1 week before

immunoadsorption

The immunosuppressive regimen consisted of:The immunosuppressive regimen consisted of:


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Splenectomy of the recipient wasSplenectomy of the recipient wasperformed due to theperformed due to the

role of the spleen in anti-A/B antibodyrole of the spleen in anti-A/B antibody

production.production. Immunosuppressive triple therapy wasImmunosuppressive triple therapy was

based on calcineurin inhibitors, steroids andbased on calcineurin inhibitors, steroids andantimetabolites, differing among centres,antimetabolites, differing among centres,

on the basis of which additionalon the basis of which additionalimmunosuppressive agents, such asimmunosuppressive agents, such asantilymphocyte globulin, deoxyspergualinantilymphocyte globulin, deoxyspergualinor cyclophosphamide, were administered.or cyclophosphamide, were administered.

Antibody removal was usually notAntibody removal was usually notperformed after transplantationperformed after transplantation


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Since 2004, a desensitization protocolSince 2004, a desensitization protocol

without splenectomy starting 4 weekswithout splenectomy starting 4 weeks

prior to transplantation, includingprior to transplantation, including Double filtration plasmapheresis, anti-CD20Double filtration plasmapheresis, anti-CD20treatment, mycophenolate mofetil and steroids,treatment, mycophenolate mofetil and steroids,

was introduced, showing a successful short-was introduced, showing a successful short-

term outcome.term outcome. No additional post-operative antibody removalNo additional post-operative antibody removal

or administration of IVIG was performed .or administration of IVIG was performed .


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Combination of the following therapies before transplantationCombination of the following therapies before transplantation::

a Plasmapheresis to physically removePlasmapheresis to physically removeantibodies.antibodies.

a Immunoglobulin also called gammaImmunoglobulin also called gammaglobulin, which appears to decreaseglobulin, which appears to decreaseantibody activity destructive to the graft.antibody activity destructive to the graft.

a Splenectomy the spleen concentrates BSplenectomy the spleen concentrates Blymphocytes around its blood vessels tolymphocytes around its blood vessels tofight infection so removing it in a personfight infection so removing it in a personwith very high levels of antibodies wardswith very high levels of antibodies wardsoff graft rejection.off graft rejection.

a Anti-CD20 antibody (rituximab) depletesAnti-CD20 antibody (rituximab) depletes

the CD20 protein, which is found on thethe CD20 protein, which is found on thewall of most B cells.wall of most B cells.


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a Recipient antibodies are monitored during theRecipient antibodies are monitored during thefirst two weeks following transplantation andfirst two weeks following transplantation andtreated by plasmapheresis if they rise above atreated by plasmapheresis if they rise above a

predetermined level.predetermined level.

a Like all transplant recipients, the patients mustLike all transplant recipients, the patients mustremain on drugs that suppress the immuneremain on drugs that suppress the immunesystem, such as thymoglobulin, tacrolimus,system, such as thymoglobulin, tacrolimus,

mycophenolate mofetil, and prednisone, for asmycophenolate mofetil, and prednisone, for aslong as the grafted kidney survives.long as the grafted kidney survives.


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ABO-incompatible kidney

transplantation offers a safe

option to perform renal

transplantation successfully in

patients whose only livingdonor is blood-group-

incompatible.

ABO-incompatible kidneytransplantation offers a safe

option to perform renal

transplantation successfully in

patients whose only livingdonor is blood-group-

incompatible.


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a Each of us has a set of histocompatibilityEach of us has a set of histocompatibilitymolecules that are like fingerprints in thatmolecules that are like fingerprints in thatprobably no other human being has anprobably no other human being has an

identical set.identical set.

a A positive crossmatch to theA positive crossmatch to thehistocompatibility antigens blood test meanshistocompatibility antigens blood test means

you have antibodies against donor HLAyou have antibodies against donor HLAantigensa decidedly negative result forantigensa decidedly negative result foranyone waiting for transplant.anyone waiting for transplant.


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a In the case of transplants,In the case of transplants,

however, they are responsible forhowever, they are responsible for

antibody-mediated rejection of aantibody-mediated rejection of atransplanted organ because theytransplanted organ because they

act as antigens when introducedact as antigens when introduced

into a different person.into a different person.


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a Mayo initiated its clinical trial for a positiveMayo initiated its clinical trial for a positive

cross match kidney transfusion in Januarycross match kidney transfusion in January

2000.2000.

a Protocols similar to those of ABO incompatibleProtocols similar to those of ABO incompatible

transplant were employed.transplant were employed.

a Protocols from Johns Hopkins and theProtocols from Johns Hopkins and the

University of Maryland were very similar toUniversity of Maryland were very similar to

ABO protocols.ABO protocols.


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a Both positive-crossmatch and ABO-incompatible living-Both positive-crossmatch and ABO-incompatible living-

donor kidney transplantations can be performed withdonor kidney transplantations can be performed with

survival rates approaching those of negative-crossmatchsurvival rates approaching those of negative-crossmatch

and ABO-compatible transplantations.and ABO-compatible transplantations.

a However, for them to become more successful, additionHowever, for them to become more successful, addition

methods to prevent antibody-mediated damage need tomethods to prevent antibody-mediated damage need to

developed.developed.


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a These include therapies that result inThese include therapies that result inprolonged suppression of antibody formation.prolonged suppression of antibody formation.

a The lab is currently evaluating the necessity ofThe lab is currently evaluating the necessity ofsplenectomy versus intensive therapy withsplenectomy versus intensive therapy withplasmapheresis and anti-CD20 monoclonalplasmapheresis and anti-CD20 monoclonalantibody.antibody.

a The next phase is to test therapies that mayThe next phase is to test therapies that maydecrease antibodies.decrease antibodies.

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antibody barriers1