Minor Histocompatibility Antigens: from Transplantation Problems to Therapy of Cancer

doi:10.1016/j.humimm.2006.03.012

Human Immunology

Volume 67, Issue 6, June 2006, Pages 433-438

https://doi.org/10.1016/j.humimm.2006.03.012 Get rights and content

Abstract

The idea of transferring healthy marrow for the therapeutic treatment of the various diseases of the blood and of the immune system made a significant contribution to controlling diseases and to advancing modern clinical sciences. The first series of bone marrow transplantations in the 1960s were confronted with severe complications. It became clear that matching for the human leukocyte antigen (HLA) system between donor and recipient significantly improved the clinical results. Nonetheless, an unacceptable percentage of severe complications remained that is mainly attributable to non-HLA histocompatibility systems, i.e., minor histocompatibility antigens. Observations in the 1970s that minor histocompatibility antigens cause serious problems in human bone marrow transplantation laid the basis for their use as curative antigens in stem cell transplantation to date. Thus, the allo-immune T cell activities caused by minor histocompatibililty antigen disparities between HLA-matched donor and recipient can now be applied for the benefit of the transplant patient.

Section snippets

Background

Pioneering physicians in the USA and in France showed the feasibility of transfering healthy bone marrow for the treatment of patients suffering from various forms of hematological diseases such as severe aplastic anemia and leukemia and severe deficiencies of the immune system [1, 2]. In the case of leukemia, chemo-radiotherapy eliminating the major tumor load of the patient precedes the transplant. Bone marrow transplantation with donors matching the recipient's HLA system increased the

From the Patient to the Laboratory

In humans, mHag studies have predominantly been performed in the HLA-identical SCT setting. The first report on the possible influence of mHags on the outcome of BMT was observed in a situation wherein a female aplastic anemia patient rejected the BM transplanted from her HLA-identical brother. Cytotoxic T cells (CTLs) isolated from the patient's blood lysed cells that were HLA matched and of male origin [4, 5]. The T cell reactivity observed in the host-versus-graft direction in this case was

Important Characteristics of Human Minor Histocompatibility Antigens

The most crucial characteristic of mHags is that they are alloantigens. The “level” of the individual minor H allogenicity in a particular HLA-matched patient/donor pair is further determined by the mHag allelic difference between patient and donor and by the mHag tissue distribution.

Hence, the mHag frequencies in the population define the overall impact of mHags on the development of GvHD and GvL after HLA-matched SCT. Only mHags with interesting frequencies in the population (thus not the

From the Laboratory to the Patient

The “allo-ness” of the mHags justifies their application as tumor target molecules. As opposed to tumor-associated self-antigens, the complexes of MHC and allo-target peptide are likely to be more immunogenic than the MHC and self-target complexes. Moreover, mH alloantigens are not subject to self-tolerance; they are membrane expressed and tissue and/or cell specific. These characteristics of mHags meet the prerequisites for tumor therapy in the context of HLA-matched SCT.

The establishment of

Minor Histocompatibility Antigens as “Vaccines” for Cancer

In this strategy, mHag peptides can be used to vaccinate the selected mHag SC donor and/or boost the SC recipient post allogeneic SCT. Donor vaccination may involve ethical problems. This leaves the administration of mHag peptides to the patient as the currently most feasible procedure. The rationale behind this strategy is to administer patient's self-mHags (with or without mHag peptide-pulsed donor-derived antigen-presenting cells (APCs)) to the patient after SCT. Herewith the mHag-specific

Future Directions

In addition to the analyses of the mHag allo-immune responses in the physiological setting of pregnancy and their consequences for SC and CB-T, mHag disparity may also result in neutralizing their own responses. Namely, mHag HA-1-specific T regulator (Treg) cells have been isolated from the peripheral blood of a long-term kidney allograft recipient [49]. These cells specifically inhibited mHag HA-1 CTLs present simultaneously in the same patient. Herewith a novel characteristic for human minor

Acknowledgments

I thank Lothar Hambach, Eric Spierings, and Gitte Möller for their support.

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Minor Histocompatibility Antigens: from Transplantation Problems to Therapy of Cancer

Abstract

Section snippets

Background

From the Patient to the Laboratory

Important Characteristics of Human Minor Histocompatibility Antigens

From the Laboratory to the Patient

Minor Histocompatibility Antigens as “Vaccines” for Cancer

Future Directions

Acknowledgments

Blood

Blood

Immunity

Blood

Blood

Lancet

Curr Opin Immunol

Semin Oncol

Blood

Blood

Blood

Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy

N Eng J Med

Transfusions et graffés de moetle osseuse homologue chez des humains irradiés a haute dause accidentellement

Rev Francaise Etudes Clin Biol

Aplastic anemia treated by marrow transplantation

Lancet

Alloimmunity to human H-Y

Lancet

Y-antogen killing by T cells of women is restricted by HLA

Nature

A minor transplantation antigen detected by MHC-restricted cytotoxic T lymphocytes during graft-versus-host disease

Nature

Induction of minor Histocompatibility antigen specific T helper, but not T cytotoxic response is dependent on the source of antigen presentation cells

Human Immunol

Characterization of naturally occurring minor histocompability paptides including H-4 and H-Y

Science

Cellular peptide composition governed by major histocompability complex class I molecules

Nature

Maternally transmitted antigen of mice: a model transplantation antigen

Annu Rev Immunol

Identification of a Graft-versus-Host Disease-associated human minor Histocompatibility antigen

Science

The minor Histocompatibility antigen HA-1: a diallelic gene with a single amino acid polymorphism

Science

Identification of a Novel HLA-B60-Restricted T Cell Epitope of the Minor Histocompatibility Antigen HA-1 Locus

J Immunol