CHAPTER 42: HLA and ABO Desensitization

HUMAN LEUKOCYTE ANTIGEN MOLECULES

• Highly polymorphic antigens expressed on the surface of cells

• Have crucial roles in defense against foreign pathogens and in tumor immune surveillance

• Antibodies against these antigens can develop as a result of pregnancy, transplantation, or blood transfusion

• Human leukocyte antigen (HLA) sensitization adversely affects both access to and the outcomes of transplantation

• Improved identification of HLA molecules and of the specificity of HLA antibodies has improved transplant graft survival

• Desensitization of anti-HLA antibodies is essential to enable meaningful progress in the field of transplantation and increase the likelihood that a patient will receive a transplant offer.

DESENSITIZATION

Goal

• Lower donor-specific antibody (DSA) levels at a range safe for transplantation

  • HLA antibodies below a positive complement-dependent cytotoxicity (CDC) antihuman globulin (AHG) cytotoxic crossmatch

  • Isohemagglutination immunoglobulin G (IgG) titers ≤16

Two Major Protocols

• High-dose (1–2 g/kg) intravenous immunoglobulin (IVIg)

  • Protocols for both live and deceased donor transplant recipients

  • 2 g IVIg/kg infused monthly until:

    • Favorable crossmatch results

    • Four doses (main effect seen after the first dose)

  • Has a durable effect on HLA antibody that lasts for months and increases transplant rates

  • It may be more effective when combined with anti-CD20

  • Allows for transplantation of sensitized patients with no live donors

• Plasmapheresis with low dose IVIg (100 mg/kg)

  • Hopkins protocol includes every-other-day plasmapheresis and low-dose IVIg

  • Plasmapheresis depletes HLA antibody, and IVIg prevents new endogenous synthesis

  • At least two posttransplant sessions

    • More sessions may be required based on DSA levels

    • Aim to achieve DSA strength below positive flow crossmatch

  • DSA levels rebound within days of discontinuing plasmapheresis if the transplant is not performed, so this is usually only an option for patients with live donors

  • DSA is often eliminated after posttransplant plasmapheresis, especially DSA to class I antigens

  • Twenty-five percent of patients will have an antibody-mediated rejection (AMR) after desensitization, and most of these AMR episodes respond to additional plasmapheresis and IVIg

  • Combining desensitization with kidney-paired donation can reduce the initial (pre-desensitization) strength (level) of DSAs and result in improved outcomes

Anti-CD20

• Used selectively in high-risk donor–recipient combinations

  • Depletes memory B cells in secondary lymphoid tissues and peripheral blood

  • May prevent recall responses for which memory exists

  • Does not affect long-lived plasma cells that are residents in the bone marrow and do not express CD20

  • Splenectomy remains a rescue option in severe AMR (approximately 8% of cases)

Novel Approaches to Desensitization

• Novel agents have shown great promise for both desensitization and the treatment of AMR when combined with standard-of-care therapies

• Examples include:

  • Proteasome inhibitors such as bortezomib, which disrupt the normal intracellular protein degradation process

  • Complement inhibitors such as eculizumab, which binds to complement protein C5 and blocks both the classical and lectin pathways

  • Interleukin (IL-6) or IL-6 receptor blockers such as clazakizumab and ...