**2. Transplantation as a therapeutic approach**

HSCT offers potentially curative therapy for patients suffering from various congenital or acquired malignant or nonmalignant lymphohematopoietic diseases.

These mainly include myeloid malignancies such as myeloproliferative neoplasms (MPNs), in particular myelofibrosis (MF). Others include myelodysplastic syndromes (MDS), myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPNs), chronic and acute myeloid leukemias (CML and AML).

Also, lymphoid diseases such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin, and non-Hodgkin lymphomas, as well as various types of anemias (Fanconi's anemia, severe aplastic anemia) are highly ranked among [2, 3].

#### **2.1. Factors affecting the decision and outcome of HSCT**

Several factors should be taken into account in order to estimate the benefit/risk of HSCT compared to other treatment options, such as chemotherapy [4].

These include disease characteristics, age along with related comorbid conditions and donor availability, followed by race, socioeconomic status and financial fitness.

These can be widely viewed as pretransplantation, transplantation-associated and posttransplantation risk factors, although they cannot be classified in such a way, because the transplantation protocol is affected by pre-transplantation conditions and they may both affect post-transplantation events. The latest comprise of graft-versus-host disease (GVHD), infections, and disease relapse.

Donor suitability is a major issue affecting the course of HSCT and shall be thoroughly analyzed.

#### *2.1.1. Donor suitability*

implementation in molecular diagnostics altogether contributed toward characterizing such

Novel pharmaceutical approaches, such as targeted therapies, optimized chemotherapy regimens, radiotherapy, and others have been developed. Yet, many of these diseases still present poor survival outcomes. In such cases, hematopoietic stem cell transplantation (HSCT) is considered as final resort therapeutic approach, whenever all other options have failed [1].

The success of HSCT depends on various factors that should be taken into consideration in advance. Reduced immunological reaction is such a major factor. This is only accomplished when donor and recipient of the graft are immunologically compatible. During the previous decades, immunology and molecular biology techniques have been moving toward delineat-

During the past few years, the advent of high throughput sequencing technologies has helped move toward this direction with a much faster pace. In this chapter, we will review the past,

HSCT offers potentially curative therapy for patients suffering from various congenital or

These mainly include myeloid malignancies such as myeloproliferative neoplasms (MPNs), in particular myelofibrosis (MF). Others include myelodysplastic syndromes (MDS), myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPNs), chronic and acute myeloid

Also, lymphoid diseases such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin, and non-Hodgkin lymphomas, as well as various types of anemias

Several factors should be taken into account in order to estimate the benefit/risk of HSCT

These include disease characteristics, age along with related comorbid conditions and donor

These can be widely viewed as pretransplantation, transplantation-associated and posttransplantation risk factors, although they cannot be classified in such a way, because the transplantation protocol is affected by pre-transplantation conditions and they may both affect post-transplantation events. The latest comprise of graft-versus-host disease (GVHD), infec-

present, and future of these technologies in this particular area of research.

acquired malignant or nonmalignant lymphohematopoietic diseases.

(Fanconi's anemia, severe aplastic anemia) are highly ranked among [2, 3].

ing the biological mechanism of this compatibility.

46 Umbilical Cord Blood Banking for Clinical Application and Regenerative Medicine

**2. Transplantation as a therapeutic approach**

**2.1. Factors affecting the decision and outcome of HSCT**

compared to other treatment options, such as chemotherapy [4].

availability, followed by race, socioeconomic status and financial fitness.

leukemias (CML and AML).

tions, and disease relapse.

conditions.

#### *2.1.1.1. Human leukocyte antigen (HLA) system*

It is well established that donor suitability is mainly dictated by the genomic loci of major histocompatibility complex (MHC), located on the short arm of chromosome 6 in humans. This highly polymorphic genetic system encodes for the major histocompatibility antigens that comprises the human leukocyte antigen (HLA) system.

These cell surface antigens where first characterized using allo-antibodies (allo-Abs) against leukocytes. Although they are clinically important in HSCT, their primary biological function is the regulation of immune response [5].

Only 30% of patients have HLA-matched-sibling donor (HLA-MSD) which is the gold standard for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The remaining 70% relies on alternative sources of stem cells.

These include suitable volunteer HLA-matched-unrelated donors (HLA-MUD), one-locus HLA-mismatched-unrelated donors (HLA-mmUD), HLA-haploidentical donors (HLAhaplo) (half matched donor, typically a parent or other relative), or umbilical cord blood (UCB) units [6–8].

The success of HSCT highly depends on the HLA compatibility between graft and patient. This is because recognition of HLA allelic differences by T lymphocytes of the patient increases the risk of graft rejection, GVHD, slow or incomplete immune reconstitution, and consequent risk of lethal opportunistic infections [9].

Other important prognostic impact factors are age, sex, cytomegalovirus (CMV) serostatus, and natural-killer (NK) cells allo-reactivity [6].

#### *2.1.1.2. Killer inhibitory receptor (KIR) types*

KIR types comprise yet another genetic characteristic of donor that affects transplantation outcomes during allo-HSCT.

NK cells are lymphoid cells of the innate immunity that contribute to GVT, but not GVHD. Their function is characterized by interaction of surface receptors with their cognate ligands on target cells. KIRs are such receptors whose genetic loci constitutes of multiple genes that encode for them, just like the respective genetic loci of HLA genes.

Also, there is considerable genetic diversity in the KIR genetic locus, like with MHC.

Upon binding of some of the KIRs with their ligands, NK cell function is inhibited, while other KIRs promote activation of NK cells after engagement with their cognate ligand.

Most of the KIR-ligands are HLA-class I molecules.

KIRs can be subdivided into two main categories based on the strength of their affinity to the ligands. It has been observed that Group A binds more effectively than group B.

KIRs seem to play important role in transplantation outcome. Transplant recipients missing KIR-ligands, especially in the absence of allo-reactive T cells (e.g., in T-cell-depleted HLAhaplo HSCT) were proven to present decreased rate of disease recurrence and improved survival.

To conclude, the presence of activating KIR genes in the donor favorably affects recurrence rates in myeloid, but not lymphoid neoplasms [10].
